Abstract
Reduced expression of GATA4, a transcriptional factor for structural and cardioprotective genes, has been proposed as a factor contributing to the development of cardiomyopathy. We investigated whether the reduction of cardiac GATA4 expression reported in diabetes alters the expression of downstream genes, namely, atrial natriuretic peptide (ANP), B-type natriuretic, peptide (BNP), and α- and β-myosin heavy chain (MHC). db/db mice, a model of type 2 diabetes, with lean littermates serving as controls, were studied. db/db mice exhibited obesity, hyperglycemia, and reduced protein expression of cardiac GLUT4 and IRAP (insulin-regulated aminopeptidase), the structural protein cosecreted with GLUT4. Hearts from db/db mice had reduced protein expression of GATA4 (~35%) with accompanying reductions in mRNA expression of ANP (~40%), BNP (~85%), and α-MHC mRNA (~50%) whereas expression of β-MHC mRNA was increased by ~60%. Low GATA4 was not explained by an increased ligase or atrogin1 expression. CHIP protein content was modestly downregulated (27%) in db/db mice whereas mRNA and protein expression of the CHIP cochaperone HSP70 was significantly decreased in db/db hearts. Our results indicate that low GATA4 in db/db mouse heart is accompanied by reduced expression of GATA4-regulated cardioprotective and structural genes, which may explain the development of cardiomyopathy in diabetes.
Highlights
Diabetes is a major risk factor in the development of cardiovascular disease [1]
GATA4 is highly expressed in cardiomyocytes where it regulates the transcription of α- and β-myosin heavy chain (MHC) composition, atrial natriuretic (ANP), and B-type natriuretic (BNP) peptides, which are important in cardiac function, blood pressure regulation, and cardioprotection [9, 10]
This reduction in GLUT4 was associated with a concomitant decrease in mRNA (60%, P < 0.01) and protein expression (75%, P < 0.001) of insulin-regulated aminopeptidase (IRAP) which codistributes with GLUT4
Summary
Diabetes is a major risk factor in the development of cardiovascular disease [1]. Impairment of left ventricular function is frequent in patients with type 2 diabetes even in the absence of ischemic, hypertensive, and valvular heart disease [2, 3]. Disturbances in energy metabolism and vascular endothelial function play a role in the development of left ventricular dysfunction, altered transcription of genes encoding for contractile and structural proteins contribute to the cardiovascular risk of diabetic patients [5,6,7,8]. GATA4 is highly expressed in cardiomyocytes where it regulates the transcription of α- and β-myosin heavy chain (MHC) composition, atrial natriuretic (ANP), and B-type natriuretic (BNP) peptides, which are important in cardiac function, blood pressure regulation, and cardioprotection [9, 10]. GATA4 levels are markedly reduced and recent evidence indicates that cardiac GATA4 degradation is increased in diabetes [15, 16]
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