BackgroundDiabetes is associated with changes in myocardial stress-response pathways and is recognized as an independent risk factor for cardiac remodeling. Using spontaneously diabetic Goto Kakizaki rats as a model of type 2 DM we investigated whether post-translational modifications in the Akt - FOXO3a pathway, Sirt1 - p53 pathway and the mitogen activated protein kinase p38 regulator are involved in post-infarct cardiac remodelingMethodsExperimental myocardial infarction (MI) was induced by left anterior descending coronary artery ligation in spontaneously diabetic Goto-Kakizaki rats and non-diabetic Wistar controls. Cardiac function was studied by echocardiography. Myocardial hypertrophy, cardiomyocyte apoptosis and cardiac fibrosis were determined histologically 12 weeks post MI or Sham operation. Western blotting was used to study Caspase-3, Bax, Sirt1, acetylation of p53 and phosphorylation of p38, Akt and FOXO3a. Electrophoretic mobility shift assay was used to assess FOXO3a activity and its nuclear localization.ResultsPost-infarct heart failure in diabetic GK rats was associated with pronounced cardiomyocyte hypertrophy, increased interstitial fibrosis and sustained cardiomyocyte apoptosis as compared with their non-diabetic Wistar controls. In the GK rat myocardium, Akt- and FOXO3a-phosphorylation was decreased and nuclear localization of FOXO3a was increased concomitantly with increased PTEN protein expression. Furthermore, increased Sirt1 protein expression was associated with decreased p53 acetylation, and phosphorylation of p38 was increased in diabetic rats with MI.ConclusionsPost-infarct heart failure in diabetic GK rats was associated with more pronounced cardiac hypertrophy, interstitial fibrosis and sustained cardiomyocyte apoptosis as compared to their non-diabetic controls. The present study suggests important roles for Akt-FOXO3a, Sirt1 - p53 and p38 MAPK in the regulation of post-infarct cardiac remodeling in type 2 diabetes.
Our findings suggest a therapeutic role for oral levosimendan in prevention of postinfarct heart failure and cardiac remodeling in type 2 diabetes and underscore the importance of sustained cardiomyocyte apoptosis and induction of cellular senescence in the pathogenesis.
Heme oxygenase-1 (HO-1) is a cytoprotective enzyme, which regulates cell proliferation and has potential antifibrogenic properties. In the present study, we investigated the effects of pre-emptive HO-1 induction by cobalt protoporphyrin IX on the healing of myocardial infarction in rats. The proliferation and repair of cardiac cells was assessed by immunostaining of Ki67 and proliferating cell nuclear antigen, and apoptosis of cardiomyocytes by terminal deoxynucleotidyl transferase dUTP nick end labelling. Compared with control hearts, HO-1 induction reduced apoptosis and increased proliferation and repair of cardiomyocytes in the infarct border area during the first few days after infarction. Concomitantly, HO-1 decreased accumulation and proliferation of fibroblasts, and down-regulated procollagen type I expression in the infarct area. Furthermore, HO-1 increased expression of the anti-inflammatory cytokine, transforming growth factor-β1, suggesting that the cardioprotective effect of HO-1 in the early phase of infarct healing may result partly from the suppression of the inflammatory response. In the remote myocardium, HO-1 inhibited both proliferation and apoptosis of cardiomyocytes, attenuated heart failure-induced increase in the repair of cardiomyocytes and decreased perivascular fibrosis, thereby potentially alleviating adverse ventricular remodelling. The cardioprotective effects of HO-1 in the late phase of infarct healing may be mediated partly by down-regulation of the profibrotic connective tissue growth factor (CTGF), as HO-1 decreased CTGF expression at week 4. In conclusion, our findings suggest an important role for HO-1 in maintaining cellular homeostasis in the postinfarction heart. Modulation of the HO-1 pathway may provide a new therapeutic approach to enhance the recovery of myocardial infarction and protect against pathological myocardial changes.
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