PPARγ activator, rosiglitazone: Is it beneficial or harmful to the cardiovascular system?

Table 1 Reports of the beneficial effects of rosiglitazone on the cardiovascular system in pre-clinical and clinical studies

Models	Dose of rosiglitazone	Major findings	Interpretation	Ref.
Cultured neonatal rat cardiomyocytes	5 μmol/L; pretreated for 30 min before stimulation with Ang II (1 μmol/L) for 48 h	Inhibited Ang II-induced upregulation of skeletal α-actin and ANP genes, and prevent an increase in cell surface area	Rosiglitazone involved in the inhibition of cardiac hypertrophy	[27]
Isolated and cultured neonatal rat ventricular myocytes	1, 5, 10 μmol/L; pretreated for 48 h	Accelerated Ca2+ transient decay rates	Cardioprotective effects of rosiglitazone may be mediated via NF-κB	[43]
		Increased SERCA2 mRNA levels
		Upregulation of IL-6 secretion
		Enhanced TNF-α- and lipopolysaccharide-induced NF-κB-dependent transcription
Isolated and cultured adult rat ventricular myocytes	10-8-10-5 mol; pretreated for 24 h	Did not increase protein synthesis	Rosiglitazone did not directly induce cardiomyocyte hypertrophy in cardiomyocytes	[30]
		Did not attenuate hypertrophic response to noradrenaline, phorbol-12-myristate13-acetate and endothelin-1
Cultured neonatal rat ventricular myocytes	10 μmol/L; pretreated for 24 h	Inhibited the endothelin-1-induced increase in protein synthesis, surface area, calcineurin enzymatic activity, and protein expression	Rosiglitazone inhibited endothelin-1-induced cardiac hypertrophy via calcineurin/nuclear factor of activated T-cells pathway	[29]
		Inhibited the nuclear translocation of NFATc4
		Enhanced the association between PPARγ and calcineurin/nuclear factor of activated T-cells
Cultured rat cardiomyoblast cell line H9c2(2-1)	100 μmol/L; pretreated for 24 h	Increased expression of heme oxygenase 1	Rosiglitazone had cardioprotective effects against oxidative stress	[40]
		Increased cell viability under oxidative stress induced by H2O2
Cultured neonatal rat cardiac fibroblasts	0.1, 1, 10 μmol/L pretreated for 48 h	Inhibited cardiac fibroblast proliferation	Rosiglitazone could prevent myocardial fibrosis	[37]
		Increased connective tissue growth factor expression
		Decreased nitric oxide production induced by advanced glycation endproducts
Cultured neonatal rat ventricular myocytes	1 μmol/L; pretreated for 30 min prior to H2O2 treatment	Decrease cell apoptosis	Rosiglitazone protected cells from oxidative stress through upregulating Bcl-2 expression	[42]
		Increase Bcl-2 protein content
Cultured neonatal rat cardiac myocytes	0.1, 1, 3, 10, 30 μmol/L; pretreated for 30 min before hypoxia	Decreased cytoplasmic accumulation of histone-associated DNA fragments	Rosiglitazone protected cardiac myocytes against I/R injury by facilitating Akt rephosphorylation	[35]
		Increased reoxygenation-induced rephosphorylation of Akt
		Did not alter phosphorylation of the MAP kinases ERK1/2 and c-Jun N-terminal kinase
Fatty Zucker rats	7-7.5 μmol/L per kilogram po; 9-12 wk	Decreased systolic blood pressure	Rosiglitazone prevented the development of HT and endothelial dysfunction associated with insulin resistance	[45]
		Decreased fasting hyperinsulinemia
		Improved mesenteric arteries contraction and relaxation
Rats with I/R injury	3 mg/kg per day po; pretreated for d; 1 and 3 mg/kg iv given during I/R	Improved left ventricular systolic pressure, dP/dtmax and dP/dtmin	Rosiglitazone decreased infarct size and improved contractile dysfunction during I/R possibly via inhibition of the inflammatory response	[46]
		Reduced neutrophils and macrophages accumulation
		Reduced the infarct size
		Downregulation of CD11b/CD18
		Upregulation of L-selectin on neutrophils and monocytes
Fatty Zucker rats with I/R injury (Ex vivo model)	3 mg/kg po; 7 or 14 d prior to isolated perfuse heart study	Normalized the insulin resistance	Rosiglitazone protected obese rat heart from I/R injury	[44]
		Restored GLUT4 protein levels
		Improved contractile function
		Prevented greater loss of ATP
I/R injury in isolated perfused normal and STZ- induced diabetic rat hearts (Ex vivo model)	1 μmol/L given prior to ischemia; 10 μmol/kg per day po after STZ injection for 4 wk	Inhibited activating protein-1 DNA-binding activity	Rosiglitazone attenuated postischemic myocardial injury in isolated rat heart	[34]
		Inhibited of Jun NH2-terminal kinase phosphorylation
		Reduced lactate levels and lactate dehydrogenase activity
Sprague-Dawley rats	5 mg/kg per day po; 7 d	Reduced systolic blood pressure	Rosiglitazone prevented the development of hypertension and endothelial dysfunction	[31]
		Reduced vascular DNA synthesis, expression of cyclin D1 and cdk4, AT1 receptors, vascular cell adhesion molecule-1, and platelet and endothelial cell adhesion molecule, and NF-κB activity
T2DM mice	3 mg/kg per day po; 7 d	Did not affect serum glucose and insulin	Rosiglitazone enhanced nitric oxide mediation of coronary arteriolar dilations via attenuating oxidative stress in T2DM mice	[28]
		Increased serum 8-isoprostane and dihydroethydine-detectable superoxide production
		Enhanced catalase and reduced NAD(P)H oxidase activity
		Did not affect SOD activity
Hypercholesterolemic New Zealand rabbits with I/R injury	3 mg/kg per day po; 5 wk prior to I/R	Attenuated postischemic myocardial nitrative stress	Rosiglitazone attenuated arteriosclerosis and prevented I/R-induced myocardial apoptosis	[38]
		Restored a beneficial balance between pro- and anti-apoptotic MAPK signaling
		Reduced postischemic myocardial apoptosis
		Improved cardiac functional recovery
Zucker diabetic fatty rats with I/R injury	3 mg/kg per day po; 8 d prior to I/R	Reduced blood glucose, triglycerides, and free fatty acids levels	Rosiglitazone protected heart against I/R injury	[26]
		Enhanced cardiac glucose oxidation
		Increased Akt phosphorylation (Akt-pS473) and its downstream targets (glycogen synthase kinase-3β and FKHR-pS256) (forkhead transcription factor)
		Reduced apoptotic cardiomyocytes and myocardial infarct size
Sprague-Dawley rats with I/R injury	3 mg/kg per day po; 7 d prior to I/R	Reduced infarct size	Rosiglitazone attenuated myocardial I/R injury possibly via increase expression of AT2 and inhibition of p42/44 MAPK	[41]
		Decreased myocardial expression of AT1 receptors
		Increased AT2 mRNA and protein expression
		Inhibited p42/44 MAPK
		Did not alter Akt1 expression
Sprague-Dawley rats with I/R injury	3 mg/kg per day po for 8 wk prior to I/R	Improved left ventricular dP/dtmax and dP/dtmin	Rosiglitazone had a beneficial effect on post-infarct ventricular remodeling, but had a neutral effect on mortality	[32]
		Inhibited myocardial angiotensin II and aldosterone
		No significant effects on myocardial AT1 and AT2 mRNA
WT and eNOS knockout mice with I/R injury	3 mg/kg ip; retreated for 45 min prior to I/R	WT mice: increased the recovery of left ventricular function and coronary flow following ischemia	Rosiglitazone protected the heart against I/R injury via nitric oxide by phosphorylation of eNOS	[48]
		eNOS knockout mice: suppressed the recovery of myocardial function following ischemia
Isolated perfused hearts from T2DM mice	23 mg/kg per day po; pretreated for 5 wk	Normalized plasma glucose and lipid concentrations	Rosiglitazone improved cardiac efficiency and ventricular function	[50]
		Restored rates of cardiac glucose and fatty acid oxidation
		Improved cardiac efficiency due to decrease in unloaded myocardial oxygen consumption
		Improved functional recovery after low-flow ischemia
WT and APN knockdown/knockout mice with myocardial infarction	20 mg/kg per day po; pretreated 72 h prior to MI and continuously treated until 7 and 14 d	Improved the postischemic survival rate of WT mice at 14 d of treatment	APN was crucial for cardioprotective effects of rosiglitazone in myocardial infarction	[57]
		Increased adipocyte APN expression
		Elevated plasma APN levels
		Reduced infarct size
		Decreased apoptosis and oxidative stress
		Improved cardiac function
Hypercholesterolemic rats	4 mg/kg per day po; pretreated for 5 mo	Reduced Ang II level	Rosiglitazone protected the heart against cardiac hypertrophy via improved lipid profile, reduced Ang-II and increase AT2 expression	[54]
		Upregulated AT2
		Improved lipid metabolism
Mice with I/R injury	3 mg/kg per day po; pretreated for 14 d prior to I/R	Reduced ratio of infarct size to ischemic area (area at risk)	Cardioprotective effects of rosiglitazone against I/R injury were mediated via a PI3K/Akt/GSK-3α-dependent pathway	[59]
		Reduced the occurrence ventricular fibrillation
		Attenuated cardiac apoptosis
		Increased levels of p-Akt and p-GSK-3α
T2DM patients (n = 21)	4 mg/d; 6 mo	Weight loss (first 12 wk)	Rosiglitazone amplified some of the positive benefits of lifestyle intervention	[55]
		Decreased waist circumference
		Decreased systolic and diastolic blood pressure
		Reduced HbA1c
Randomized, double-blind, placebo-controlled study in T2DM (n = 357)	4 or 8 mg/d; 26 wk	Reduced C-reactive protein, matrix metalloproteinase-9 and white blood cell levels	Rosiglitazone had beneficial effects on overall cardiovascular risk	[49]
		Did not alter interleukin-6 level
Randomized, double-blind in CAD patients without diabetes (n = 40, control = 44)	4 mg/d for 8 wk ollowed by 8 mg/d for 4 wk	Reduced E-selectin	Rosiglitazone reduces markers of endothelial cell activation and levels of acute-phase reactants in CAD patients without DM	[56]
		Reduced von Willebrand
		Reduced C-reactive protein & fibrinogen
		Reduced homeostasis model of insulin resistance index
		Elevation of LDL and triglyceride level
Randomized, double-blind, placebo-controlled study in T2DM with CAD patients (n = 54)	4-8 mg/d; 16 wk	Improved glycemic control and whole-body insulin sensitivity	Rosiglitazone facilitated myocardial glucose storage and utilization in T2DM with CAD patients	[36]
		Increased myocardial glucose uptake in both ischemic and non-ischemic regions
Randomized controlled trial in patients with impaired glucose tolerance (n = 2365, control = 2634)	8 mg/d; 3 yr	Facilitated normoglycemic	Rosiglitazone reduced incidence of T2DM and increased normoglycemia	[47]
		Did not alter cardiovascular event
Randomized, double-blind, placebo-controlled trial in patients with T2DM (n = 70, control =16)	8 mg/d; 6 mo	Decreased plasma glucose and HbA1c with a trend to decrease HOMA index	Rosiglitazone improved endothelial function and C-reactive protein in patients with T2DM	[51]
		Decreased C-peptide and fasting insulin
		Reduced C-reactive protein
		Improved endothelium-dependent dilation
Randomized, controlled trial in patient with T2DM with CAD (Rosiglitazone; n = 25)	4 mg/d; 12 wk	Decreased insulin resistance	Rosiglitazone prevented arteriosclerosis by normalizing metabolic disorders and reducing chronic inflammation of the vascular system	[58]
		Decreased pulse wave velocity
		Reduced plasma levels of C-reactive protein and monocyte chemoattractant protein 1
Prospective and cross-sectional study in T2DM (Rosiglitazone; n = 22, metformin/rosiglitazone; n = 100)	Treated with rosiglitazone 6 mo	Decreased endotoxin	Lower endotoxin and higher adiponectin in the groups treated with rosiglitazone may be responsible for the improved insulin sensitivity	[39]
		Increased adiponectin levels
Comprehensive meta-analysis of randomized clinical trials (n = 42922, control = 45483)	Results of 164 trials with duration > 4 wk	The OR for all-cause and cardiovascular mortality with rosiglitazone was 0.93 and 0.94, respectively	Rosiglitazone did not increase risk of MI or cardiovascular mortality	[52]
		The OR for nonfatal MI and heart failure with rosiglitazone was 1.14 (0.9-1.45) and 1.69 (1.21-2.36), respectively
		The risk of heart failure was higher when rosiglitazone was administered as add-on therapy to insulin

Ang: Angiotensin; ANP: Atrial natriuretic peptide; OR: Odds ratio; T2DM: Type 2 diabetes mellitus; Hb: Hemoglobin; HOMA: Homeostatic Model of Insulin Resistance; CAD: Coronary artery disease; WT: Wild-type; APN: Adiponectin; eNOS: Endothelial nitric oxide synthase; GSK: Glycogen synthase kinase; LDL: Low density lipoprotein; AT: Angiotensin receptor type; SOD: Superoxide dismutase; MAPK: Mitogen-activated protein kinase; PI3K: Phosphatidyl inositol-3-kinase; STZ: Streptozotocin; I/R: Ischemia/reperfusion; TNF: Tumor necrosis factor; IL: Interleukin; NF: Nuclear factor; SERCA: sarcoendoplasmic reticulum calcium ATPase; HT: Hypertension; NFAT: nuclear factor of activated T cells; ERK: Extracellular signal-regulated kinase; PPAR: Peroxisome proliferator-activated receptor; MI: Myocardial infarction.

Table 2 Reports of the adverse effects of rosiglitazone on the cardiovascular system in pre-clinical and clinical studies

Model	Dose of rosiglitazone	Major findings	Interpretation	Ref.
Isolated and cultured vascular smooth muscle cells	1-10 μmol/L; incubated for 24 h	Induced cell death in a concentration-dependent manner	Rosiglitazone induced apoptotic cell death through an ERK1/2-independent pathway	[17]
		Increased caspase 3 activity and the cytoplasmic histone-associated DNA fragmentation
		PD98059 (MAPKK inhibitor) did not abolish rosiglitazone induced ERK1/2 activation (proapoptotic effects)
Rats with I/R injury	3 mg/kg per day po; pretreated for 14 d prior to I/R	Did not reduce left ventricular infarct size or hypertrophy	Rosiglitazone did not prevent left ventricular remodeling, but was associated with increased mortality after myocardial infarction	[21]
		Increased mortality rate
		Improved ejection fraction and prevented an increase left ventricular end diastolic pressure
Swine with I/R injury	3 mg/kg per day po; pretreated for 8 d prior to I/R	Increased expression of PPARγ	Rosiglitazone had no cardioprotective effects in a swine model of myocardial I/R injury	[25]
		Had no effect on myocardial contractile function
		Did not alter substrate uptake and proinflammatory cytokines expression
PPARγ-knockout (CM-PGKO) mouse	10 mg/kg per day po; 4 wk	Increased phosphorylation of p38 mitogen-activated protein kinase	Rosiglitazone caused cardiac hypertrophy at least partially independent of PPARγ in cardiomyocytes	[15]
		Induced phosphorylation of extracellular signal-related kinase 1/2
		Did not affect phosphorylation of c-Jun N-terminal kinases
		Induced cardiac hypertrophy
Wild type and PPARγ overexpression mice	10 mg/kg per day po; 15 d	Increased lipid accumulation	Rosiglitazone and PPARγ overexpression could be harmful to cardiac function	[24]
		Increased size of the heart
		Decreased fractional shortening
		Increased CD36 expression
Swine with I/R injury	0.1, 1.0 10 mg/kg iv; pretreated for 60 min	Attenuated MAP shortening during ischemia by blocking cardiac KATP channels	Rosiglitazone promoted onset of ventricular fibrillation during cardiac ischemia	[20]
		Increased propensity for ventricular fibrillation during myocardial ischemia
Sprague-Dawley rats	15 mg/kg per day po; 21 d	Induced eccentric heart hypertrophy associated with increased expression of ANP, BNP, collagen I and III and fibronectin	Rosiglitazone induced cardiac hypertrophy via the mTOR pathway	[16]
		Reduced heart rate and increased stroke volume
		Increased heart glycogen content, myofibrillar protein content and turnover
		Reduced glycogen phosphorylase expression and activity
Meta-analysis in T2DM (n = 15 565, control = 12 282)	Received rosiglitazone more than 24 wk	Increased the risk of myocardial infarction	Rosiglitazone increased in the risk of myocardial infarction and borderline increased in risk of cardiovascular death	[11]
		Increased cardiovascular death incidence
RECORD study (n = 4447)	Received rosiglitazone with mean follow-up time of 3.75 yr	Increased the risk of heart failure	Rosiglitazone increased risk of heart failure, but did not increase the risk of cardiovascular death or all cause mortality	[18]
RECORD study (n = 4447)	Received rosiglitazone with mean follow-up time of 5.5 yr	Increased the risk of heart failure	Rosiglitazone increased risk of heart failure	[65]
			Suggestion of contraindication for rosiglitazone to be used in patients developing symptomatic heart failure
Case-control analysis of a retrospective cohort study (n = 159 026)	Treated with TZDs at least 1 yr	Increased risk of heart failure	Rosiglitazone was associated with risk of heart failure, acute myocardial infarction, and mortality	[19]
		Increased mortality
		Increased risk of acute myocardial infarction
Retrospective, double-blind, randomized clinical studies with rosiglitazone (n = 14 237)	Received rosiglitazone 24-52 wk	Increased heart failure incidence	Rosiglitazone increased the risk of heart failure and myocardial infarction	[13]
		Increased events of myocardial ischemia
A meta-analysis of randomized controlled trials (n = 6421, control = 7870)	Received rosiglitazone at least 12 mo	Increased risk of myocardial infarction and heart failure	Rosiglitazone increased risk of myocardial infarction and heart failure, without increased risk of cardiovascular mortality	[23]
		No increased risk of cardiovascular mortality

I/R: Ischemia/reperfusion; PPAR: Peroxisome proliferator-activated receptor; T2DM: Type 2 diabetes mellitus; RECORD: Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes; ANP: Atrial natriuretic peptide; BNP: B-type natriuretic peptide; ERK: Extracellular signal-regulated kinase; TZD: Thiazolidinedione; mTOR: Mammalian Target of Rapamycin pathway