Impact of sodium-glucose cotransporter-2 inhibitors on pulmonary vascular cell function and arterial remodeling

Abstract

Sodium-glucose cotransporter-2 (SGLT-2) inhibitors represent a cutting-edge class of oral antidiabetic therapeutics that operate through selective inhibition of glucose reabsorption in proximal renal tubules, consequently augmenting urinary glucose excretion and attenuating blood glucose levels. Extensive clinical investigations have demonstrated their profound cardiovascular efficacy. Parallel basic science research has elucidated the mechanistic pathways through which diverse SGLT-2 inhibitors beneficially modulate pulmonary vascular cells and arterial remodeling. Specifically, these inhibitors exhibit promising potential in enhancing pulmonary vascular endothelial cell function, suppressing pulmonary smooth muscle cell proliferation and migration, reversing pulmonary arterial remodeling, and maintaining hemodynamic equilibrium. This comprehensive review synthesizes current literature to delineate the mechanisms by which SGLT-2 inhibitors enhance pulmonary vascular cell function and reverse pulmonary remodeling, thereby offering novel therapeutic perspectives for pulmonary vascular diseases.

Key Words: Sodium-glucose cotransporter-2 inhibitors; Pulmonary vascular endothelial cells; Pulmonary vascular smooth muscle cells; Pulmonary artery remodeling; Right heart dysfunction; Cardiovascular disease

Core Tip: Sodium-glucose cotransporter-2 (SGLT2) inhibitors are innovative antidiabetic agents that lower blood glucose by promoting its excretion via the kidneys. Beyond their glucose-lowering effects, SGLT2 inhibitors have demonstrated significant cardiovascular benefits in clinical trials. Emerging basic science research indicates that SGLT2 inhibitors also positively impact pulmonary vascular health. They enhance the function of pulmonary vascular endothelial cells, inhibit the proliferation and migration of pulmonary smooth muscle cells, reverse pulmonary arterial remodeling, and help maintain hemodynamic stability. This review consolidates current findings on the mechanisms by which SGLT2 inhibitors improve pulmonary vascular cell function and arterial remodeling, suggesting new therapeutic possibilities for pulmonary vascular diseases.

INTRODUCTION

Sodium-glucose cotransporter-2 (SGLT-2) inhibitors, representing an innovative class of hypoglycemic agents, function by impeding renal glucose reabsorption, thereby facilitating blood glucose reduction. The nineteenth century witnessed French chemist C. Pettersen's isolation of phlorizin from apple root bark, revealing its glucose-lowering properties in diabetic animals. However, its limited SGLT1/SGLT2 selectivity and glycosidase-mediated hydrolytic susceptibility precluded its therapeutic implementation[1]. Subsequent SGLT2 research revealed its pivotal role in renal glucose reabsorption. SGLT-2 inhibitors emerged as promising antidiabetic agents, distinguished by their reduced hypoglycemic risk and beneficial weight-reduction properties. The 2012 European Medicines Agency approval of dapagliflozin marked the inaugural SGLT-2 inhibitor[2]. Currently, seven SGLT-2 inhibitors are available globally: Dapagliflozin, tofogliflozin, canagliflozin, empagliflozin, luseogliflozin, ipragliflozin, and sotagliflozin. In China, canagliflozin, dapagliflozin, and empagliflozin have secured the United State Food and Drug Administration approval for clinical implementation. SGLT-2 inhibitors have revolutionized diabetes management through their dual mechanism of preventing renal glucose reabsorption and promoting glucose excretion. Beyond glycemic control, these agents enhance insulin sensitivity, facilitate weight reduction, optimize blood pressure, and improve metabolic parameters in diabetic patients. Their therapeutic potential extends to diabetic nephropathy, heart failure, and hepatic fibrosis. Research demonstrates their efficacy in reducing proteinuria, mitigating cardiovascular and cerebrovascular risks, and decelerating renal insufficiency progression[3].

The cardiovascular benefits of SGLT-2 inhibitors have garnered substantial attention, demonstrating efficacy in type 2 diabetes mellitus management independent of direct glucose modulation[4]. These inhibitors have emerged as frontline therapeutics in heart failure management, achieving natriuretic and osmotic diuretic effects through SGLT-2-mediated glucose reabsorption inhibition[5]. They induce autophagy and reduce epicardial adiposity by optimizing cardiomyocyte calcium processing and enhancing cardiac energy metabolism[6]. Through metabolic parameter optimization, including lipid and uric acid profiles, SGLT-2 inhibitors attenuate cardiovascular risk factors, reduce heart failure hospitalization rates, and decrease all-cause mortality[7-10]. Their protective effects against diabetic complications and cardiovascular disease stem from the amelioration of low-grade systemic and tissue inflammation[11]. They demonstrate synergistic cardio-renal protection, reducing diabetic nephropathy proteinuria and optimizing glomerular filtration rates[5,12-14]. A landmark clinical trial by the University of Toronto Health Network[15] and Hulst et al[16] has enhanced understanding of SGLT-2 inhibitor mechanisms and safety across diverse patient populations. Certain SGLT-2 inhibitors have received expanded Food and Drug Administration approval for reducing the risk of type 2 diabetes mellitus and heart disease. Emerging evidence suggests SGLT-2 inhibitors’ therapeutic potential in pulmonary hypertension and right heart failure (RHF). Fundamental studies indicate their capacity to suppress pulmonary smooth muscle proliferation and migration, ameliorate arterial remodeling, induce pulmonary arterial relaxation, and reduce pulmonary arterial pressure across various pulmonary hypertension models[17-19].

SGLT-2 INHIBITORS

Structure and function of SGLT2

SGLT2, a 60 kDa protein predominantly expressed in renal tubules, comprises 565 amino acids arranged in 12 transmembrane segments with dual cytoplasmic regions. Its extracellular N-terminus features glycosylation sites for glucose binding, while its C-terminus remains intracellular. SGLT2 forms functional dimeric or tetrameric structures facilitating glucose transport through conformational changes. Sodium ion transport energetically drives efficient glucose transport via SGLT2, primarily in proximal tubules where approximately 90% of glucose reabsorption occurs, with SGLT1 managing the remaining 10% in renal and small intestinal tissues.

Mechanism of cardiovascular protective action of SGLT-2 inhibitors

SGLT-2 inhibitors demonstrate multifaceted cardiovascular protection through optimization of cardiomyocyte metabolism, ventricular load modulation, cardiomyocyte Na⁺/H⁺ exchange inhibition, adipokine, and cytokine profile modification, and attenuation of cardiomyocyte necrosis and myocardial fibrosis[20]. They reduce cardiac volume load through osmotic diuresis and natriuresis[21], primarily affecting interstitial fluid without inducing hypotension[22-25]. These agents exhibit angiotensin converting enzyme inhibitor-like effects, protecting vascular endothelium and decelerating coronary atherosclerosis while maintaining electrolyte homeostasis and renal function[26-29]. They exhibit trimetazidine-like effects, transforming myocardial energy metabolism, elevating serum erythropoietin concentrations, and enhancing ketone body availability[30,31]. Additionally, they demonstrate calcium antagonist-like properties, optimizing blood pressure, body weight, and metabolic parameters[32-34].

While SGLT2 expression is documented in endothelial cells and cardiomyocytes[35,36], its presence in human cardiac tissue remains predominantly unreported[37,38]. Matrix metalloproteinases (MMPs) are implicated in cardiovascular pathogenesis[39,40], with phloridin demonstrating MMP inhibition. SGLT-1 and SGLT-2 inhibitors, as phloridin derivatives[41], show potential in reversing MMP-2 overexpression[42]. However, definitive evidence linking MMPs to SGLT-2 inhibitors’ cardiovascular protection remains elusive. While canagliflozin’s dual SGLT-1/SGLT-2 inhibition enhances urinary glucose excretion, its impact on cardiac volume load requires further investigation[43].

Groundbreaking research by Jiang et al’s team at Tongji University, utilizing various knockout mouse myocardial infarction models, demonstrated empagliflozin’s significant enhancement of post-infarction survival rates, ventricular function, and reduction in cardiac fibrosis and myocardial cell hypertrophy[44]. Their glucose deprivation model revealed empagliflozin’s direct cardiomyocyte interaction through membrane accumulation and Na(+)/H(+) exchanger 1 (NHE1) protein interaction, improving autophagic cell death responses and cardiomyocyte contractility[45].

PULMONARY VASCULAR CELL FUNCTION

Characteristics and roles of cells in the pulmonary vasculature

The pulmonary circulatory system serves as a critical interface for oxygen-rich blood transport between the heart and lungs. Pulmonary vascular cells, comprising endothelial cells, smooth muscle cells, and fibroblasts, constitute the vessel walls’ inner, medial, and outer layers, maintaining structural and functional integrity. These cellular components orchestrate complex physiological functions within the pulmonary circulatory system. Endothelial cells, predominating the vessel inner wall, exhibit secretory capabilities, synthesizing crucial bioactive substances including nitric oxide, prostacycline, and MMPs. These molecules maintain vasomotor equilibrium, inhibit platelet aggregation, and modulate inflammatory responses. Under hypoxic or inflammatory conditions, endothelial cells facilitate angiogenesis and repair through autocrine and paracrine mechanisms.

Smooth muscle cells, primarily located in the vessel media, regulate vasomotor function. Larger vessels feature predominantly smooth muscle cells, while microvessels contain precursor cells or pericytes. These cells achieve precise pulmonary vascular tension regulation through intracellular calcium modulation and bioactive substance secretion. Fibroblasts, situated in the vessel’s outer layer, synthesize matrix components like collagen and elastin, maintaining vascular stability and elasticity. They possess myofibroblast differentiation capability, participating in vascular remodeling and fibrosis processes.

Relationship between pulmonary vascular cells and cardiovascular disease

Pulmonary vascular cell dysfunction can precipitate diverse pathophysiological cascades, including pulmonary hypertension, pulmonary edema, and pulmonary atherosclerosis. These alterations not only compromise pulmonary function but also significantly impact cardiovascular homeostasis. Notably, pulmonary hypertension can induce right ventricular hypertrophy and heart failure, while pulmonary arterial atherosclerosis may elevate coronary artery disease risk. The relationship can be clearly shown in Figure 1.

Figure 1  Relationship between pulmonary vascular cells and cardiovascular disease.

Pulmonary vascular endothelial dysfunction

Endothelial dysfunction represents a pivotal factor in pulmonary hypertension and RHF pathogenesis, integrally involved in pulmonary arterial remodeling[46]. This dysfunction manifests through impaired endothelium-dependent vasodilation, elevated oxidative stress, chronic inflammation, enhanced leukocyte adhesion, and accelerated endothelial senescence, affecting systemic and pulmonary hemodynamics alongside renal and coronary circulation. Endothelial stiffening reduces nitric oxide production, promoting vascular rigidity and smooth muscle contraction[47], with Rho family GTPases playing crucial roles in endothelial function and vasoconstriction in pulmonary hypertension patients[48].

Studies on human immunodeficiency virus (HIV)-associated pulmonary hypertension have revealed elevated vascular endothelial growth factor (VEGF) and platelet-derived growth factor expression in HIV-infected T lymphocytes. The HIV-1 envelope glycoprotein 120 stimulates endothelin-1 (ET-1) and tumor necrosis factor-alpha (TNF-α) production, potentially mediating vasoconstriction, inflammation, and vascular remodeling[49]. ET-1 exhibits vasoconstrictive, pro-inflammatory, and pro-mitotic properties, stimulating free radical formation and platelet activation[50-52].

TNF-α induces endothelial cell apoptosis and barrier dysfunction, reducing extracellular resistance and enhancing apoptotic processes through increased myosin light chain phosphorylation and stress fiber formation[53-56]. EndoMT serves as a key promoter of endothelial dysfunction, while mitochondrial dysfunction significantly contributes to endothelial impairment and pulmonary hypertension. Mitochondrial-targeted interventions and caloric restriction show therapeutic potential[57].

Pulmonary hypertension in sickle cell disease manifests through occlusive vascular smooth muscle hyperplasia, endothelial abnormalities, and in situ thrombosis[58]. Elevated endothelial activation markers, including vascular cellular adhesion molecule-1 (VCAM-1), correlate with decreased nitric oxide (NO) bioavailability[59]. VEGF and VEGF receptor 2 play critical roles in endothelial cell proliferation and differentiation[60]. The activation of nuclear factor of activated T-cells 1 in human pulmonary valve endothelial cells is a specific activation of VEGF signaling mediated by VEGF receptor 2, which may be an important mechanism for maintaining pulmonary valve function by enhancing endothelial cell proliferation[61]. R-spondin3, primarily produced by endothelial cells[62], demonstrates significant regulatory functions. Studies indicate that lung EC-specific R-spondin3 manipulation affects EC proliferation and injury responses, with overexpression promoting endothelial recovery through leucine-rich repeats containing G protein-coupled receptor 4-dependent β-catenin and integrin-linked kinase signaling pathways[63]. The PH-COPD[64] and PERFECT[65] studies continue to advance understanding of pulmonary vascular pathophysiology and therapeutic strategies.

Inflammatory response

Inflammatory processes play a fundamental role in cardiovascular disease pathogenesis, with pulmonary vascular cell dysfunction potentially mediating cardiovascular pathology through inflammatory pathways. Direct exposure of vascular endothelial cells to ultrafine particles triggers inflammatory cascades, with particle composition determining inflammatory intensity[66]. In mild COPD, smoking-related inflammatory processes correlate with aberrant pulmonary vascular development, characterized by endothelial dysfunction and intimal thickening[67].

Mast cells demonstrate regulatory effects on pulmonary vascular remodeling in pulmonary hypertension, with pulmonary chymase activity positively correlating with vascular remodeling outcomes[68]. The modulation of immune cell populations, including decreased mast cells, macrophages, and T cells, contributes to improved hemodynamics and vascular remodeling in idiopathic pulmonary hypertension[69]. Transcriptomic analyses reveal G protein-coupled receptor 4 receptor activation’s role in stimulating endothelial inflammatory responses[70,71]. Inflammatory signaling pathways, particularly those involving MMP-9, intercellular adhesion molecule-1 (ICAM-1), and cyclooxygenase-2, demonstrate significant regulatory roles in pulmonary vascular pathology[72]. Hypoxic exposure induces intravascular wall inflammation, promoting structural remodeling and sustained vasoconstriction[73]. Mesenchymal stromal cells in hypoxic pulmonary hypertension models inhibit endothelial cell signal transducer and activator of transcription 3 signaling through exosome release, highlighting paracrine protective mechanisms[74]. Oxidative stress, concurrent with inflammatory responses, mediates air pollution’s adverse pulmonary and cardiovascular effects[75]. The vessel outer membrane, particularly fibroblasts, demonstrates key regulatory functions in pulmonary vascular homeostasis[76].

C-type natriuretic peptide demonstrates therapeutic potential in monocrotaline-induced pulmonary hypertension, reducing monocyte/macrophage infiltration and enhancing endothelial nitric oxide synthase (eNOS) content[77]. Glucagon-like peptide-1 analogs exhibit multiple beneficial effects, including inflammation suppression, vascular reactive oxygen species (ROS) reduction, and microcirculation improvement[78,79]. Together, these studies confirm the complex interplay between lung blood vessel cells and inflammatory responses in various lung diseases.

Effect on hemodynamics

Vascular cell dysfunction-induced vasomotor imbalance significantly impacts cardiovascular hemodynamics[80]. Large animal studies have demonstrated SERCA2a gene therapy’s positive effects on chronic retrocapillary pulmonary hypertension[81]. Post-coronavirus disease 2019 persistent dyspnea correlates with pulmonary vascular dysfunction[82], while exercise-induced pulmonary hypertension in sickle cell disease reflects increased pulmonary arterial pressure and resistance[83].

Porcine ET studies provide valuable insights into pulmonary and systemic vascular bed activity[84]. Pulmonary hypertension (PH) due to left heart failure hemodynamics monitoring primarily utilizes right cardiac catheterization, with cardiac magnetic resonance providing supplementary evaluation. Elevated ET-1 and adrenomedullin levels positively correlate with PH severity[85]. Oral sildenafil, a pulmonary vasodilator, has demonstrated benefits in improving exercise capacity and alleviating dyspnea in chronic obstructive pulmonary disease patients[86]. Balloon pulmonary angioplasty for chronic thromboembolic pulmonary hypertension significantly enhances patient hemodynamics and reveals key relationships between pulmonary vascular compliance and pressure-flow dynamics[87]. Additionally, daglizin has been shown to markedly improve pulmonary hemodynamics in heart failure patients with reduced ejection fraction[88].

IMPACTS OF SGLT-2 INHIBITORS ON PULMONARY VASCULAR CELL FUNCTION

SGLT-2 inhibitors and pulmonary vascular endothelial function

The pathogenesis of pulmonary hypertension remains incompletely understood, characterized by endothelial cell dysfunction, apoptosis, medial smooth muscle cell proliferation, and microangiogenesis. SGLT-2 inhibitors demonstrate comprehensive effects on endothelial cell function, modulating proliferation, migration, differentiation, survival, and senescence[88-92]. Twenty-four studies have established SGLT2’s direct, glucose-independent effects on endothelial function. Animal models demonstrate SGLT-2 inhibitors’ capacity to reduce oxidative stress and inflammatory responses, restore endothelium-dependent vasodilation, and regulate angiogenesis in both diabetic and non-diabetic contexts[92]. These agents suppress ICAM-1, VCAM-1, and various interleukin (IL) expressions, ameliorating widespread endothelial dysfunction[26,93-99].

Cytokines secreted by endothelial cells

Pulmonary vasomotor regulation involves complex interactions between endothelial calcium concentrations, NO and prostaglandin I2 release, and endothelium-derived factors. ETB receptor expression in pulmonary vascular endothelial cells mediates crucial regulatory functions, with ET-1 and thromboxane A2 elevation during endothelial dysfunction promoting pulmonary arterial contraction and smooth muscle proliferation[100]. ETB activation induces vasodilator release and ET-1 clearance through Gq/11 signaling pathways[101].

In patients with pulmonary hypertension, eNOS and NO bioavailability in pulmonary vascular endothelial cells is reduced, while ET-1 levels are elevated. Protein kinase C enhances threonine phosphorylation of eNOS, leading to decreased NO levels. β-blockers can inhibit protein kinase C activity, thereby restoring NO bioavailability in endothelial cells[102]. Endogenous NO may activate potassium ion channels on the cell membrane via protein kinase G (PKG), reduce cytoplasmic free calcium concentration, promote membrane hyperpolarization, inhibit Ca²⁺ influx, and ultimately induce pulmonary vasodilation[103].

In PA-induced human umbilical vein endothelial cells, phloretin partially alleviates endothelial dysfunction by inhibiting SGLT1 and SGLT2 expression, activating the phosphoinositol-3 kinase/protein kinase B/eNOS signaling pathway, and increasing NO release[104]. SGLT-2 inhibitors ameliorate endothelial dysfunction through multiple mechanisms, including NADPH oxidase/ROS signaling modulation, epidermal growth factor receptor/Src/Rho kinases regulation, and protease-activating receptor 2-mediated eNOS-dependent vasodilation[105,106]. Dapagliflozin demonstrates particular efficacy in reducing diastolic calcium and sodium overload while reversing endothelial activation[107]. Empagliflozin exhibits protective effects through NHE-1 inhibition and protein kinase B pathway activation[108,109].

Sustaining eNOS phosphorylation and endothelium-dependent relaxation has been shown to improve microvascular density and perfusion[110]. Englaglizin additionally reduces expression levels of p53, p21, p16, tissue factor, VCAM-1, SGLT-1, and SGLT-2, while increasing eNOS expression, thereby enhancing endothelial function, reducing arterial aging, inhibiting cardiac remodeling, and lowering superoxide production in the thoracic aorta of db/db mice with acetylcholine-impaired endothelial function. Although endothelial and vascular smooth muscle cell (VSMC) proliferation was not increased, vasodilation was significantly improved[111,112].

However, the EMBLEM trial demonstrated that enoglizin did not directly improve endothelial dysfunction[113]. Both enoglizin and daglizin restored NO bioavailability and endothelial cell function by reducing mitochondrial oxidative damage and inhibiting ROS production, though they did not impact TNFα-induced eNOS expression or the expression of signaling, barrier, and adhesion molecules in endothelial cells[114-116]. Furthermore, nanomaterials (NPs) substantially upregulated SGLT2 and ENA, while significantly decreasing NPs-induced senescence markers, including β-gal activity, cell cycle arrest, and the aging markers p53 and p21. SGLT2 inhibition prevented NPs-induced endothelial senescence and upregulated eNOS expression, contributing to improved vascular function[117].

Fluid shear stress

Fluid shear stress activates mechanosensitive pathways in pulmonary vascular endothelial cells, regulating vasoconstriction and dilation[118]. Activation of specific cationic channels can lead to calcium inflow and depolarization of cell membrane, which leads to cell contraction and increased pulmonary vascular pressure[118]. Two distinct mechanosensitive channel types - shear-activated potassium channels and stretch-activated cation channels - mediate these responses. SGLT-2 inhibitors modulate SERCA2a and Cav1.2 protein expression while inhibiting RYR2, thereby maintaining calcium homeostasis[119,120].

Daglipzin alleviates endothelial dysfunction and mitigates microvascular injury during cardiac ischemia/reperfusion injury by normalizing the XO-SERCA2-CaMKII-cofilin pathway[121]. Furthermore, daglipzin significantly improves systemic endothelial function, arterial stiffness, and renal resistance index. This effect, which is independent of blood pressure changes, may be mediated by a reduction in oxidative stress in sodium-stable conditions, indicating a rapid and direct beneficial impact on the vascular system[122,123].

Energy metabolism of endothelial cells

Aberrant endothelial cell energy metabolism exacerbates pulmonary vascular remodeling through multiple mechanisms. Oxidative stress plays a central role in this process, with mitochondrial remodeling and autophagy serving as key pathological features[124]. In pulmonary hypertension, apical cells migrate to hypoxic microenvironments, relying on glycolysis to fuel cell proliferation[125]. During microangiogenesis, glucose transporter interactions initiate glycolytic pathways, with glycogen serving as a crucial energy reserve[126].

The DEFENCE study demonstrated that dagaglizin therapy improves endothelial function by reducing urinary 8-hydroxy-2’-deoxyguanosine levels, thereby alleviating oxidative stress[127]. Dagaglizin attenuates TNF-α and hyperglycemia-induced increases in intercellular adhesion molecule-1, vascular cell adhesion molecule-1, plasminogen activator inhibitor type 1, and nuclear factor-kappaB while enhancing glucose uptake, reducing pro-inflammatory chemokine secretion, and significantly decreasing vascular adhesion molecule expression and phosphorylated-IkappaBalpha. This action reduces macrophage infiltration in the vascular wall, thus improving endothelial function[128,129].

In endothelial cells under oxidative stress, daglipzin reduces ROS production by restoring eNOS activity, increasing NO bioavailability, and activating sirtuin 1. This reverses endothelial-mesenchymal transformation, regulates mitochondrial function through the sirtuin 1/peroxisome proliferator-activated receptor gamma coactivator 1 alpha pathway, and improves endothelial dysfunction in obese patients[130-132]. Enaglipzin shifts myocardial energy utilization from glucose to ketone bodies, free fatty acids, and branched-chain amino acids, enhancing myocardial energy efficiency and ventricular systolic function[45]. Englipzin also protects endothelial cell mitochondria under ischemia/reperfusion stress[133].

Englaglizin’s ability to activate adenosine monophosphate-activated protein kinase (AMPK) plays a crucial role in safeguarding the endothelium from hyperglycemia-induced damage. By inhibiting mitochondrial fission, reducing mitochondrial ROS production, and controlling oxidative stress through AMPK activation, it preserves cardiac microvascular endothelial cell (CMEC) barrier function. This prevents CMEC senescence, promotes CMEC migration, and supports F-actin depolymerization[108]. Englaglitzin also mitigates high glucose-induced expression of endothelial cells markers and oxidative stress, increases eNOS and NO production, reduces VCAM-1 and tissue factor expression, and lowers local angiotensin system activity. It reduces glucose uptake and prevents high glucose- and H₂O₂-induced endothelial cell aging, as well as SGLT1 and SGLT2 expression[134].

Caglizin significantly inhibits CD40 upregulation, downregulates Nox organizer 1 gene expression, decreases ICAM-1 and nitrotyrosine, increases platelet endothelial cell adhesion molecule-1 immunoreactivity, and alleviates endothelial dysfunction post-ischemia/reperfusion[135]. Caglipzin further improves apoptosis marker expression (Bax/Bcl-2 ratio) and genes associated with myocardial oxidative stress, significantly boosting endothelium-dependent vasodilation gene expression[136]. Through activation of the α1 AMPK/p38/mitogen-activated protein kinase/heat shock protein 27 pathway, caglipzin enhances endothelial cell function[137]. Additionally, cagliglizin increases antioxidant expression (superoxide dismutase-2, catalase, glutathione peroxidase), endothelial markers [platelet endothelial cell adhesion molecule-1, VEGF-A, (3) inducible NOS], and CD34+ cell function[138]. SGLT-2 inhibitors also improve endothelial barrier dysfunction by inhibiting NHE1 and reducing ROS through NADPH-oxidase inhibition[139].

Endothelial cells exposed to coronavirus disease 2019 plasma with high cytokine levels experience SGLT2 upregulation via pro-inflammatory cytokines IL-1β, IL-6, and TNF-α, leading to endothelial dysfunction, senescence, nuclear factor-kappaB activation, inflammation, platelet adhesion and aggregation, vasculovascular carcinoma factor secretion, and thrombin production[140,141]. SGLT-2 inhibitors offer clear cardiovascular benefits by ameliorating endothelial dysfunction[142]. Pulmonary endothelial cell dysfunction remains a pivotal factor in the development of pulmonary hypertension, although the disease’s diverse and complex pathogenesis warrants further investigation into the connection between SGLT-2 inhibitors and pulmonary endothelial dysfunction.

EFFECTS OF SGLT-2 INHIBITORS ON PULMONARY SMOOTH MUSCLE CELLS AND PULMONARY ARTERY REMODELING

Mechanisms of pulmonary artery remodeling

Pulmonary artery remodeling represents a critical pathophysiological process in pulmonary hypertension development, particularly evident in paradoxical adipose hyperplasia (PAH) secondary to congenital heart disease. This process manifests through arterial wall thickening, luminal narrowing, and eventual RHF. Pulmonary artery smooth muscle cell (PASMC) proliferation and intimal migration constitute core pathological mechanisms[80,143]. Recent research has identified secreted cysteine-rich acidic proteins as promoters of hypoxic pulmonary hypertension through PASMC activation[144]. Additionally, heterogeneous nuclear ribonucleoprotein A2B1 facilitates pro-proliferative and anti-apoptotic PASMC phenotypes[145,146].

The cancer theory of pulmonary hypertension suggests environmental stressors promote the development of highly proliferative, apoptosis-resistant cell clones, including smooth muscle cells and fibroblasts[147]. Hypoxia modulates pulmonary vasomotor tone through complex electro-mechanical and pharmacomechanical pathways, with intracellular calcium serving as a crucial signaling mediator[148,149].

Genetic factors, including variations in vasoactive intestinal peptide genes, may contribute to the development of pulmonary hypertension and vascular remodeling[150]. In hypoxic PASMCs, the activity and expression of glucose-6-phosphate dehydrogenase, an enzyme in the phosphopeptide pathway, is increased[151]. Certain molecules, such as interferon, inhibit smooth muscle cell proliferation to regulate hypoxic pulmonary vascular remodeling[152]. Pulmonary denervation has been shown to reduce pulmonary remodeling in an animal model of pulmonary hypertension induced by dehydroepiandrosterone[153].

A 2005 study from Hebei Medical University demonstrated that combination therapy with spironolactone, captopril, and carvedilol reversed pulmonary artery remodeling in patients with PAH associated with congenital heart disease. Additionally, ET receptor inhibition improved diastolic dysfunction and pulmonary hypertension in heart failure[148]. Sacubitril/valsartan has been shown to lower pulmonary artery pressure in heart failure patients with either preserved or reduced ejection fraction[9,154]. T valentine, a phosphodiesterase-3/4 inhibitor, inhibits smooth muscle cell migration induced by rosaline and reverses pulmonary vascular remodeling in rats[155]. Furthermore, phosphodiesterase 1 inhibitors, such as 8-methoxymethyl methyl 3-isobutyl-1-methylxanthine, have reversed elevated pulmonary artery pressure and structural remodeling in animal models[156].

Effects of SGLT-2 inhibitors on PASMCs

PASMC regulation plays a pivotal role in PAH pathogenesis. Smooth muscle cell-derived NO modulates cyclic guanosine 3’,5’-monophosphate (cGMP) levels, inducing vascular relaxation through K channel activation[68,157]. NOTCH3 signaling demonstrates essential functions in pulmonary hypertension development and smooth muscle cell proliferation[158]. Upregulation of elastase inhibitors may treat advanced pulmonary vascular disease in rats[159]. Up-regulation of phosphodiesterase 1 in pulmonary hypertension may reverse pulmonary vascular remodeling[156]. Empagliflozin significantly reduces mean pulmonary artery pressure, right ventricular systolic pressure, and pulmonary arteriole muscularization[160]. The EMBRACE-HF trial demonstrated empagliflozin’s significant reduction of pulmonary artery pressure in heart failure patients[161]. Canagliflozin exhibits remarkable effects on right ventricular systolic pressure and pulmonary arteriole wall thickening while inhibiting PASMC proliferation and migration through glycolysis inhibition and AMPK signaling pathway reactivation[162].

Currently, research on the effects of SGLT-2 inhibitors on PASMCs is limited, though these inhibitors demonstrate significant effects on VSMCs in cardiovascular applications. Englipzin induces vasodilation by activating PKG and Kv channels in vascular smooth muscle, independent of endothelial cells[163]. SGLT-2 inhibitors reduce vascular smooth muscle calcification by inhibiting thioredoxin domain-containing 5-dependent osteogenic reprogramming in the endoplasmic reticulum[164]. Englaglitzin notably inhibits calcification in VSMCs induced by osteogenic media or inorganic phosphorus[165] and alleviates hyperphosphate-induced calcification in mice via the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 anti-inflammatory pathway through AMPK activation[166].

Englipzin also improves smooth muscle cell calcification by inhibiting BHLHE40-dependent nucleotide-binding domain, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) inflammasome activation[167] and indirectly enhances DNA repair in VSMCs by reducing ROS production[168]. Daglizin decreases myosin light chain 20 phosphorylation in VSMCs, reducing Ca²⁺-induced vasoconstriction[169]. Its vasodilatory effects may involve cyclic adenosine monophosphate/protein kinase A and/or cGMP/PKG signaling pathways[170] and inhibit NLRP3/caspase-1-mediated apoptosis in VSMCs by downregulating cathepsin B[171]. Additionally, englipzin reduces IL-17A-induced proliferation and migration of human aortic smooth muscle cells by targeting TRAF3IP2/ROS/NLRP3/caspase-1-dependent secretion of IL-1β and IL-18[172].

Enoglizin significantly increases AMPK and eNOS levels in aortic tissue, decreases angiotensin II, ET-1, P-selectin, VCAM-1, and vasoactive intestinal peptide, and has a vasodilatory effect[173]. Caraglipzin inhibits VSMC proliferation and migration in the rat aorta in a concentration-dependent manner, halting VSMC growth in the G0/G1 phase and preventing S-phase entry, thereby reducing DNA synthesis and VSMC proliferation[174]. Caraglipzin also downregulates the expression of NLRP3 and its downstream signaling molecules, caspase-1 and IL-1β, in VSMCs[175], and stimulates heme oxygenase-1 expression through the ROS-nuclear factor erythroid 2-related factor 2 pathway, contributing to its cellular effects[176]. Additionally, caglipzin induces thoracic aorta dilation via SERCA pumps and Kv channels[177], while egaglipzin promotes arterial relaxation by activating Kv channels (primarily Kv7.X) and SERCA pumps, independently of other K⁺ channels and cGMP/PKG or cyclic adenosine monophosphate/protein kinase A pathways[178]. SGLT-2 inhibitors may inhibit smooth muscle cell proliferation and may relieve pulmonary hypertension.

Effect of SGLT-2 inhibitors on pulmonary artery remodeling

SGLT-2 inhibitors demonstrate significant capacity to reverse or attenuate PAH remodeling[91,179,180]. Empagliflozin reduces mitochondrial ROS and miR-193b levels while restoring nuclear factor Y α subunit/soluble guanylate cyclase activity[181]. Englipzin inhibitors reduced right ventricular systolic pressure and mitigated pulmonary artery remodeling in McT-induced PAH rats, with differential results attributed to PAH severity, duration of treatment, or pleiotropy of SGLT-2 inhibitor[176]. Canagliflozin ameliorates pulmonary artery and right ventricular remodeling in MCT-PAH rats through multiple mechanisms, including reduction of pulmonary arteriole wall thickness and vascular hypertrophy[182].

Caraglipzin inhibits the proliferation and migration of pulmonary smooth muscle cells and improves arterial remodeling by inhibiting glycolysis and reactivating AMPK signaling pathways[162]. The beneficial effect of toglazine on pulmonary artery remodeling in PH-left heart disease (LHD) was verified for the first time in vitro. The direct effect of toglazine on PASMCs can improve pulmonary vascular remodeling and reduce right cardiac load in mice PH-LHD[19]. Egaglipzin has been shown to inhibit VSMC migration, alleviate neointimal hyperplasia, and reduce vascular remodeling[183]. Daglipzin enhances Ca²⁺ handling in right ventricular cardiomyocytes, reducing ventricular arrhythmia susceptibility and improving both pulmonary artery remodeling and right heart function in PAH-induced RHF rats[184]. Additionally, intramuscular injection of sotalizine increases the expression of angiogenic factors hypoxia-inducible factor-1α, VEGF-A, and platelet-derived growth factor-BB (PDGF-BB), enhances VEGF-A and PDGF-BB secretion under hypoxic conditions, promotes the migration and proliferation of vascular endothelial and smooth muscle cells, and has potential effects on angiogenesis and inhibition of vascular remodeling[185]. PDGF-BB, a potent mitogen and chemoattractant for PASMCs, is associated with increased cell proliferation and migration, playing a crucial role in PAH progression and pulmonary artery remodeling[186,187]. Overall, targeting specific pathways involved in pulmonary vascular remodeling, such as smooth muscle cell migration and SGLT2 inhibition, may provide promising therapeutic strategies for the management of PAH and related diseases. The impacts can be seen in Figure 2. Figure 3 shows the mechanisms more directly. Further studies are needed to fully elucidate the mechanisms of action and potential benefits of these interventions in the treatment of pulmonary artery remodeling in patients with PH.

Figure 2 Impacts of sodium-glucose cotransporter-2 inhibitors on pulmonary vascular cell function and pulmonary artery remodeling. NO: Nitric oxide; SGLT2i: Sodium-glucose cotransporter-2 inhibitor.

Figure 3 Mechanisms through which sodium-glucose cotransporter-2 inhibitors modulate pulmonary vascular cell function and pulmonary artery remodeling. VSMC: Vascular smooth muscle cells; Kv channel: Voltage-gated potassium channels; PKG: Protein kinase G; AMPK: Adenosine monophosphate-activated protein kinase; Nrf2: Nuclear factor erythroid 2-related factor 2; HO-1: Heme oxygenase-1; cGMP: Cyclic guanosine 3’,5’-monophosphate; PKA: Protein kinase A; CTSB: Cathepsin B; NLRP3: Nucleotide-binding domain, leucine-rich repeat, and pyrin domain-containing protein 3; ROS: Reactive oxygen species; p-MLC20: Phospho-myosin light chain 20; TRAF3IP2: Tumor necrosis factor receptor-associated factor 3 interacting protein 2; IL: Interleukin; eNOS: Endothelial nitric oxide synthase; Ang-II: Angiotensin II; ET-1: Endothelin-1; VACM-1: Vasopressin-activated calcium-mobilizing-1; VIP: Vasoactive intestinal peptide; SGLT-2i: Sodium-glucose cotransporter-2 inhibitor; NO: Nitric oxide; 8-OHdG: 8-hydroxy-2’-deoxyguanosine; p-IκBα: Phosphorylated-IkappaBalpha; TNF: Tumor necrosis factor; miRNA: MicroRNA; ICAM-1: Intercellular adhesion molecule-1; XO-SERCA2-CaMKII-cofilin: Xanthine oxidase-sarco(endo)plasmic reticulum calcium-ATPase 2-calcium/calmodulin-dependent kinase II-cofilin.

CLINICAL RESEARCH AND PROGRESS

Role of SGLT-2 inhibitors in right heart dysfunction

Clinical trials demonstrate canagliflozin’s efficacy in reducing PAP and decreasing time increase, independent of diuretic effects[188]. Novel biomarkers show increasing utility in diagnosing and prognosticating right ventricular dysfunction, potentially offering innovative therapeutic approaches for improving both right and left ventricular function[188,189]. Transcriptomic analyses by Frisk et al[190] have revealed crucial differences between left and right ventricular responses in varying degrees of heart failure. Key biomarkers, including microRNAs, insulin-like growth factor, cardiac troponin, galectin-3, suppression of tumorigenicity 2, and growth differentiation factor-15[191], provide comprehensive assessment capabilities for heart failure, particularly in right ventricular dysfunction.

Dapagliflozin demonstrates promise in reducing cardiac fibrosis and inflammation, potentially benefiting right ventricular function[192]. It effectively reduces susceptibility to PH-induced right ventricular dysfunction by restoring calcium homeostasis in rat models[184,193]. SGLT-2 inhibitors show particular efficacy in ameliorating right ventricular dysfunction due to volume and pressure overload[194], independent of left ventricular remodeling[195-197]. Experimental models and clinical trials consistently demonstrate SGLT-2 inhibitors’ capacity to enhance right ventricular function[19,198,199]. When combined with standard heart failure therapy, these agents prove more effective than conventional PH treatments alone[195,196,200-202]. The addition of SGLT2 inhibition to established PH therapy protocols shows promising improvements in right ventricular function[202,203].

Right ventricular dysfunction and heart failure

PH and right ventricular dysfunction in HFpEF represent significant hemodynamic complications[204,205]. Right ventricular dysfunction shares pathogenic mechanisms with left ventricular dysfunction, including ischemia and capillary rarefaction due to autonomic nervous system activation and microvascular abnormalities[206]. The EMPEROR-Preservation trial demonstrated empagliflozin’s significant 29% reduction in cardiovascular death or heart failure hospitalization compared to placebo, regardless of diabetes status[22,207]. Right ventricular dysfunction severity in heart failure with reduced ejection fraction correlates proportionally with left ventricular dysfunction severity, potentially progressing to PH-LHD[208,209]. Patients exhibiting right ventricular dysfunction demonstrate significantly reduced survival rates compared to those without such dysfunction[210-212]. Right ventricular dysfunction indicates heart failure progression, with its recovery associated with improved prognosis[213]. SGLT-2 inhibitor addition to combination therapy correlates with decreased right ventricular systolic function at 3-9 months[195,196,213,214].

EMPA-REG OUTCOME TRIAL

The EMPA-REG OUTCOME trial, encompassing 7020 cardiovascular disease patients, demonstrated empagliflozin’s significant and rapid reduction in pulmonary diastolic blood pressure in heart failure patients[215]. This reduction showed progressive enhancement over time, with pulmonary arterial effects appearing independent of diuretic usage.

FUTURE RESEARCH DIRECTIONS AND CHALLENGES

Further investigation is crucial in several key areas: (1) Exploring SGLT-2 inhibitors’ therapeutic effects across diverse pulmonary vascular diseases with distinct etiologies and manifestations; (2) Investigating their potential benefits and risks in PH secondary to left heart disease; (3) Evaluating clinical relevance across different stages of pulmonary hypertension; (4) Conducting long-term studies and real-world data collection; (5) Elucidating the role of various signaling pathways (glucagon-like peptide-1, AMPK, Ca²⁺ influx, miR) in SGLT-2 inhibitor efficacy; (6) Understanding mechanisms of pulmonary vascular endothelial cell function enhancement and inflammatory response modulation; (7) Employing advanced research techniques including genomics, microbiome analysis, and immunometabolomics; (8) Investigating combination therapies with established agents; and (9) Validating long-term safety profiles.

CONCLUSION

SGLT-2 inhibitors represent a well-tolerated therapeutic class demonstrating significant efficacy in reducing pulmonary vascular disease incidence and improving patient outcomes. While their precise mechanistic pathways remain under investigation, their beneficial effects on pulmonary vascular cells and arterial remodeling are evident. These agents enhance pulmonary EC function, suppress PASMC proliferation, and attenuate pulmonary arterial remodeling. The pharmacological profile of SGLT-2 inhibitors extends beyond SGLT-2 inhibition and glycemic control, suggesting broader therapeutic potential in pulmonary vascular disease management. Further investigation of the functional, metabolic, and molecular roles of specific SGLT-2 inhibitors in vascular cells may elucidate their mechanisms in preventing pulmonary vascular disease and facilitate the development of targeted therapeutic strategies. However, conflicting data necessitates extensive additional research to validate current findings and identify optimal patient populations for this therapeutic approach.

ACKNOWLEDGEMENTS

The authors would like to express their gratitude to the scholars who participated in this study for their invaluable contributions.