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Cardiovascular complications account for significant morbidity and mortality in the diabetic population; diabetic cardiomyopathy is typified by alterations in cardiac morphology and function, independent of coronary atherosclerosis and hypertension. Several regulatory mechanisms mediate altered gene expression in DCM. Alterations in several myocardial miRs have been demonstrated in cardiac hypertrophy but the role of miR-30c in the pathophysiology of diabetes induced cardiac hypertrophy is not known. The aim of present study was to ascertain whether miR-30c may be involved in modulating expression of key genes (Cdc42, Rac1, Pak1 and p53) involved in cardiac hypertrophy in DCM.
Method: DCM was induced in Wistar rats by STZ-high fat diet combination and animals were sacrificed after 12 weeks of diabetes. The miRNA microarray was performed in cardiac tissues (n=4) and control (n=2). The expression of miR-30c, Cdc42, Rac1, Pak1 and p53genes and markers of hypertrophy (ANP and β-MHC) was studied in cardiac tissues (n = 13) and control rats (n=5). We further examined the role of miR-30c in hyperglycemia induced hypertrophy in rat myocyte cell line H9c2.
Result: STZ induced DCM Wistar rats showed interstitial fibrosis and myocyte hypertrophy with 1.6 fold increased in heart to body weight ratio (≤0.05). We observed 72 microRNAs were differentially expressed (≤0.05) by microarray analysis including decreased expression of miR-30c, which was confirmed by qRT-PCR. We further found increased expression of four specific targets of miR-30c, Rac1, Cdc42, Pak1 and p53, regulating cardiac hypertrophy, along with hypertrophy markers (ANP and β-MHC) in cardiac tissues of DCM model and was inversely related to miR-30c expression. In vitro exposure of rat myocyte cell line H9c2 to hyperglycemia showed hypertrophic changes and reduced expression of miR-30c. Finally, transfection of miR-30c mimics and inhibitor attenuates pathological cardiac hypertrophy.
Conclusion: Our results suggest that miR-30c directly down regulate Rac1, Cdc42, Pak1 and p53, a key hypertrophic proteins and thereby establish an important role in control of diabetes induced cardiac hypertrophy of diabetic myocardium.
More than 180 million people around the world are affected by Diabetes mellitus and the number is expected to increase to 300 million by 2025 (Pavan KB et al 2012). Among the vast array of vascular complications associated with diabetes, cardiovascular complications is the leading cause of morbidity and mortality through out the world22, 23. Nearly 80% of the deaths associated with diabetes are reported to be due to cardiac complications (Hayat SA et al 2004). Sustained hyperglycemia has been shown to be the key determinant for the development of the diabetic cardiomyopathy. Diabetic cardiomyopathy (DCM) is a clinical condition diagnosed when ventricular dysfunction develops in patients with diabetes in the absence of hypertension and coronary atherosclerosis (Avogaro A et al 2004). DCM is distinguished functionally by ventricular dilation, prominent interstitial fibrosis, myocytes hypertrophy, and decreased or preserved systolic function (Fonarow GC et al 2006) in the presence of a diastolic dysfunction (Severson DL et al 2004). Structurally DCM is characterized by cardiomyocytes hypertrophy and increased extracellular matrix (ECM) protein deposition, eventually leading to heart failure (Feng B et al 2008). Although the underlying causes of diabetes-associated heart disease are multifactorial (Fang ZY et al 2004) and an important role has been attributed to persistent hyperglycemia. This condition induces and activates a number of secondary messenger pathways which mediate altered gene expression in DCM. These signalling pathways are itself under the control of many regulatory molecules including microRNAs.
MicroRNAs are a group of universally present small non-coding, 18-22 nucleotide long RNAs and have emerged as one of the central players of gene regulation via mRNA degradation or by inhibition of mRNA translation (Sadakatsu Ikeda et al MOLECULAR AND CELLULAR BIOLOGY, Apr. 2009). Altered expression of several microRNAs such as miR-21, miR-1, miR-100, miR-133, miR-208a, miR-23a, miR-199b, miR-9, miR-98/let-7 (Mariko Tatsuguchi et al 2007, Danish Sayed et al 2007, Carmen Sucharov et al 2008, De-Li Dong et al 2010, Thomas E. Callis et al 2009, Zhiqiang Lin et al2009, Paula A. da Costa Martins et al 2010, Kun Wang et al 2010, Yanfei Yang et al 2010) has been reported in hypertrophied failing hearts.
However, current literature regarding role of microRNAs in cardiovascular complications of diabetes is not well understood. Identification and putative role of microRNAs targeting various signalling pathways involved in the pathogenesis of diabetes induced cardiac hypertrophy needs to be elucidated.
The p21-activated kinases (PAKs) are serine/threonine protein kinases interacting with small guanine nucleotide-binding proteins (Cdc42) of the Rho family are the downstream molecules of PI3K/Akt axis. PAKs and GTPases are key regulators that link membrane receptors to gene transcription thereby affecting diverse physiological and pathophysiological responses including contribution to cardiomyocyte hypertrophy (Oudit GY et al 2004). Role of Cdc42 and Pak1 is well documented in pressure overload-induced cardiac hypertrophy (?), leptin induced cardiomyocyte hypertrophy (Asad Zeidan et al 2011), endothelin-1 and phenylephrine induced cardiomyocyte hypertrophy (Yoshiharu Higuchi et al 2003). A recent report have also shown the role of Cdc42 and Rac1 in diabetic nephropathy (Sang-Hoon Kim et al 2012), but the role of Cdc42 and Pak1 in hyperglycemia induced cardiac hypertrophy is incompletely understood.
Here we performed miRNA microarray in diabetic heart and found significantly decreased expression of miR-30c. Moreover, no studies have yet specifically examined the role of miR-30c in the context of cardiomyocyte hypertrophy in diabetes. Therefore, the aim of present study was to ascertain whether diabetes leads to alter the expression of miRNAs including miR-30c and regulation of its bioinformatically identified targets genes Cdc42 and Pak1. In order to examine the functional importance of miRNA alteration, we also used an in vitro model of hyperglycemia-induced cardiomyocyte hypertrophy.