Atorvastatin ameliorated myocardial fibrosis by inhibiting oxidative stress and modulating macrophage polarization in diabetic cardiomyopathy

Abstract

In this editorial, we commented on the article published in the recent issue of the World Journal of Diabetes. Diabetic cardiomyopathy (DCM) is characterized by myocardial fibrosis, ventricular hypertrophy and diastolic dysfunction in diabetic patients, which can cause heart failure and threaten the life of patients. The pathogenesis of DCM has not been fully clarified, and it may involve oxidative stress, inflammatory stimulation, apoptosis, and autophagy. There is lack of effective therapies for DCM in the clinical practice. Statins have been widely used in the clinical practice for years mainly to reduce cholesterol and stabilize arterial plaques, and exhibit definite cardiovascular protective effects. Studies have shown that statins also have anti-inflammatory and antioxidant effects. We were particularly concerned about the recent findings that atorvastatin alleviated myocardial fibrosis in db/db mice by regulating the antioxidant stress and anti-inflammatory effects of macrophage polarization on diabetic myocardium, and thereby improving DCM.

Key Words: Diabetic cardiomyopathy, Statins, Macrophage, Oxidative stress

Core Tip: Satins are widely used in cardiovascular disease because of their effective effects to reduce cholesterol and stabilize arterial plaques. Reasonable statins contribute to reducing the morbidity rate of cardiovascular events. Studies have shown that statins also have anti-inflammatory and antioxidant effects. Moreover, the researchers have found anti-inflammatory and anti-oxidative stress effects of atorvastatin by regulating macrophage polarization to alleviated myocardial fibrosis and ameliorated diabetic cardiomyopathy in db/db mice.

INTRODUCTION

Diabetic cardiomyopathy (DCM) is a cardiovascular complication induced by diabetes mellitus (DM) and characterized by left ventricular hypertrophy and diastolic hypofunction, independent to cardiac dysfunction caused by coronary artery disease, hypertension and other heart diseases. It can eventually induce heart failure and thus seriously influence the quality of life of patients, and it is also one of main causes of death for diabetic patients in the developed countries[1]. The pathogenesis of DCM has not been completely clarified so far; myocardial inflammation, oxidative stress, fibrosis, mitochondrial damage, apoptosis and autophagy all may participate in the occurrence and development of DCM, of which inflammation and fibrosis are one of important mechanisms for the development of DCM. At present, there is lack of clinically effective therapies for DCM.

Statins are the first-line therapeutic drugs for cardiovascular disease, have good lipid-lowering and plaque-stabilizing pharmaceutical effects, as well as a well-established cardiovascular protecting effect, and can significantly reduce the risk of arteriosclerotic cardiovascular disease (ASCVD). In the clinical practice, statins are recommended and extensively applied to treat macrovascular complications and other cardiovascular complications of DCM and thus reduce the risk of major adverse cardiovascular event in diabetic patients[2,3]. However, the heart protection of statins is not limited to it. Several previous studies have shown that statins can improve endothelial dysfunction and heart failure of patients by declining oxidative stress and inflammatory level[4-6], and also can relieve myocardial fibrosis and relieve DCM via multiple pathways of anti-oxidative stress, anti-inflammation and anti-apoptosis[7,8].

Macrophages are a kind of innate immune cells and play an important role in maintaining the stability of immune environment, and the exudation and differentiation of monocyte-macrophages are a key link of inflammatory initiation and regulation. Macrophages have several subtypes, and unactivated M0 macrophages are differentiated into M1 and M2 macrophages after being activated by cytokines and chemotactic factors in the local microenvironment, which is known as macrophage polarization. Classical activated (M1) macrophages mainly promote inflammatory reaction and help eliminating antigens and necrotic cells, while selective activated (M2) macrophages dominantly facilitate anti-inflammatory reaction and accelerate tissue repair and remodeling. The differentiation of M1 macrophages can be induced by lipopolysaccharides, interferon-γ, transforming growth factor-β1 (TGF-β1), tumor necrosis factor-α (TNF-α) and other inflammatory factors, and that of M2 macrophages by interleukin (IL)-1, IL-4, IL-10, IL-13, and TGF-β.

Macrophage polarization imbalance is associated with several chronic inflammation-related diseases[9]. Previous studies have suggested that an imbalanced M1/M2 ratio causes excessive inflammation and thus injures the heart and promotes the occurrence of DCM[10], and the regulation of macrophage polarization exhibits good anti-fibrosis and DCM-treating effects[10-14]. It is unknown whether statins can improve DCM by regulating macrophage polarization. These studies provide us with some references and bases.

Atorvastatin ameliorated myocardial fibrosis by inhibiting oxidative stress and modulating macrophage polarization in DCM

There are no clinically specific diagnosis criteria for DCM. DCM is dominantly manifested as cardiac diastolic dysfunction and ventricular hypertrophy, and perhaps myocardial fibrosis and microvascular lesions are detected by biopsy. The db/db mice are the typical animal models of type 2 DM (T2DM) which can spontaneously develop hyper-glycemia, hyperlipemia and insulin resistance and present the typical characteristics of T2DM. After 24-wk postnatal feeding, ultrasound cardiogram showed a significant increase of left ventricular internal diameter-diastole and left ventricular internal diameter-systole but a remarkable decrease of left ventricular fractional shortening and left ventricular ejection fraction in db/db mice, which indicated cardiac diastolic and systolic dysfunction. Histological staining showed disordered and ruptured myocardial fibrous tissues, irregular cell nuclei, collagen deposition in the myocardial interstitium, and myocardial fibrosis, and there was an increase of serum creatine kinase-MB and lactate dehydrogenase levels, indicating heart injury. These changes were independent to the blood pressure and not observed in C57 mice. Based on the abovementioned findings, the 24-wk-feeding db/db mouse models presented the manifestations of DCM[15].

In db/db diabetic mice, the immunohistochemical staining of TGF-β1, TNF-α and IL-1β in myocardial tissues was consistent with their mRNA expression levels in the serum which were all significantly higher than those in the control group, while there was an evidently elevated concentration of malondialdehyde and a significantly decreased activity of superoxide dismutase in myocardial tissues; it indicated that inflammatory reaction and oxidative stress played an important role in DCM. It should be noted that these myocardial changes of DCM mice were remarkably improved after intervention with Atorvastatin Calcium, which indicated that Atorvastatin Calcium Tablets might protect the diabetic heart by relieving oxidative stress and inflammatory reaction. Further detection showed an increase of INOS⁺ (M1 macrophage marker) expression and M1/M2 ratio but a decrease of CD206⁺ (M2 macrophage marker) expression in myocardial tissues of diabetic mice; after intervention with Atorvastatin Calcium, there was increased expression of M2 macrophages and decreased expression of M1 macrophages, which indicated that the macrophages had enhanced anti-inflammatory effects. Therefore, regulating the macrophage polarization may be the mechanism that statins improve the heart function in DCM.

Clinical implications

Cardiovascular disease is a common complication and the major cause of death of T2DM, while DCM is one of important causes of death of T2DM patients in the developed countries[1]. The safe and effective cardiovascular-protecting drugs are the most important therapies in the clinical practice. The latest diabetes guidelines also emphasize the cardiovascular benefits of hypoglycemic agents[16]. Several cardiovascular-protecting hypoglycemic agents are recognized and preferred by clinicians, such as GLP-1 receptor agonist and SGLT2 inhibitor. Thus, there is a broader market for drugs with multiple therapeutic effects.

Statins, as the preferred lipid-lowering drugs for T2DM, can significantly reduce the risk of ASCVD. Statins have advantages far greater than disadvantages clinically, though some randomized controlled trial demonstrates that the application of moderate and high-intensity statins may increase the risk of DM by ≥ 11% and 12%, yet accompanied by a 10-fold growth of benefits in the major vascular outcome[17]. The latest studies also show us the additional heart protection of statins, for example, the study of Song et al[15] suggested that Atorvastatin Calcium Tablets might improve the heart function of DCM mice by regulating the anti-oxidative stress and anti-inflammatory effects of macrophage polarization on diabetic myocardium. Therefore, on the basis of either reducing the risk of cardiovascular events or improving myocardial injury caused by long-term hyperglycemia-stimulated chronic inflammation activation, the application of statins in T2DM patients seemed to be supported by sufficient reasons. However, it should be noted that the dose of atorvastatin used in this study was 10 mg/kg/d, far higher than the clinical dose (Atorvastatin Calcium Tablets: 20 mg/d (moderate dose) or 40 mg-80 mg/d (high dose)) as calculated by human body weight. As for whether the heart protection of statins is related with the dose and how to balance their protection and risks of liver injury and rhabdomyolysis, it still needs to be further discussed in the subsequent clinical studies.

CONCLUSION

The overall cardiovascular protective benefits of statin therapy in patients with T2DM far outweigh its adverse effects on blood glucose. Patients shall be informed of the risks and benefits of statins before prescription. Patients need to know that the adverse effects of statins on blood glucose can be eliminated by lifestyle and hypoglycemic drug adjustment or other measures. However, it remains unknown whether all therapeutic doses of statins have consistent cardioprotective effects, and can regulate macrophage polarization and improve diabetic myocardial fibrosis through anti-oxidative stress and anti-inflammation. We need more clinical evidence to verify whether the clinical doses of statins can achieve cardioprotective effects in diabetic patients. If there is abundant high-quality evidence showing a dual protective effect on artery and myocardium, then statins will have a clinical position further increasing in the future.