Effects of Metformin on Rosiglitazone-Induced Cardiac Hypertrophy in Mice

Abstract

Thiazolidinediones (TZD) can cause adipose tissue accumulation and myocardial hypertrophy. This study aimed to determine if combined Metformin (Glucophage) and Rosiglitazone (Avandia) could reduce the risk of heart failure caused by Rosiglitazone in BALB/c mice. BALB/c mice were treated with oral Rosiglitazone/Metformin twice daily for four weeks. Metformin or Rosiglitazone alone and non-treated mice acted as double control. Myocardial hypertrophy and associated side effects of the combined therapy were determined through isolated heart and body weights. Reverse transcription-polymerase chain reaction (RT-PCR) and Western blot were applied to evaluate expression of sulfonylurea receptor 2A (SUR2A) and Kir 6.2. The activities of peroxisome proliferator activated receptor a (PPARa) in the myocardium were also observed. Rosiglitazone/Metformin decreased body weight gain and food intake, and inhibited an increasing adipose ratio but did not reduce myocardial hypertrophy. Rosiglitazone increased Kir6.2/SUR2A, Kir6.2/SUR2B, and PPARa gene expression. The Rosiglitazone/Metformin combination further increased these gene expressions, especially PPARa. Metformin inhibits obesity but has no effect in reducing myocardial hypertrophy caused by Rosiglitazone. Whether Metformin can reduce side effects of TZDs in humans warrants further study.

Pioglitazone Attenuates Cardiac Fibrosis and Hypertrophy in a Rat Model of Diabetic Nephropathy

“…In contrast, some studies have shown that rosiglitazone, another PPAR-γ agonist, may induce cardiac hypertrophy in mice, through PPARγ-independent mechanisms. 41,44 Despite the debate regarding the effect of PPAR-γ agonists on the heart, our findings suggested that pioglitazone proved to have beneficial effects against cardiac remodeling. Obviously, these results encourage further clinical studies to validate the cardio-protective effects of pioglitazone in diabetic patients, especially those with concomitant nephropathy.…”

The Glitazars Paradox: Cardiotoxicity of the Metabolically Beneficial Dual PPARα and PPARγ Activation

“…Therefore, cardiac dysfunction of mice that overexpress cardiomyocyte PPARγ may be due to fatty acid-mediated PPARα activation, which does not occur in the aMHC-Pparg;Ppara -/mice. 173 Nevertheless, there are mixed results on PPARγ-driven activation of PPARα with some studies showing that rosiglitazone increases PPARα expression, 178 although others showing reduced expression of PPARα-target genes. 179 Along these lines, previous studies have shown that activation of either PPARα or PPARγ in cardiomyocytes is associated with accumulation of acyl-carnitines and diacylglycerols in cardiomyocytes that lead to cardiac dysfunction, 112,173 although cardiac acyl-carnitine content was reduced in the aMHC-Pparg;Ppara -/mice.…”