Key result
Hypertensive diabetic mice treated with angiotensin II developed cardiomyopathy with preserved fractional shortening, thickened left ventricle wall, extensive fibrosis, and lower KDAC activity.
In a murine model of diabetic cardiomyopathy, lower KDAC activity was observed alongside hypertrophy and fibrosis, highlighting a potential epigenetic target for future therapeutic strategies.
KDAC reduction in this diabetic cardiomyopathy model is hypothesis-generating; human studies needed before any clinical consideration.
The molecular mechanisms leading to myocyte injury, hypertrophy and dysfunction in the diabetic heart are triggered by the characteristic metabolic abnormalities, and by abnormal energetics. Lysine (K) deacetylases (KDACs) inhibition was shown to be protective in models of doxorubicin cardiotoxicity through the reduction of fibrosis, decreased inflammation and the upregulation of antioxidant defenses. KDACs' role in the pathogenesis of diabetic heart disease is unknown. We used a murine model of leptin resistance (db/db mice). These mice were treated for 1 month with angiotensin II to induce severe cardiomyopathy. Echocardiography heart morphology, biochemical markers of injury were measured in the serum and KDAC activity and signaling was measured in cardiac tissues by Western blot and real time qPCR. Hypertensive diabetic mice developed a unique cardiomyopathy characterized by preserved fractional shortening (FS), thickened left ventricle wall and smaller ventricle cavity. Histological staining revealed infiltration of immune cells and extensive fibrosis. Biochemical markers indicated metabolic syndrome. Hypertrophic markers of diabetic hearts exhibited elevated BNP and MMP2 and lower KDAC activity. Elucidating the role of epigenetic mechanisms and KDAC in the development of diabetic cardiomyopathy in order to search for therapeutic strategies based on pharmacological manipulation of histone acetylation, is needed. Funded by Tel Aviv University.
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Waldman et al. (2015) studied Diabetic cardiomyopathy. Angiotensin II was evaluated on Cardiomyopathy characteristics (echocardiography, biochemical markers, KDAC activity). Hypertensive diabetic mice treated with angiotensin II developed cardiomyopathy with preserved fractional shortening, thickened left ventricle wall, extensive fibrosis, and lower KDAC activity.
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