Eplerenone attenuated cardiac steatosis, apoptosis and diastolic dysfunction in experimental type-II diabetes

Abstract

BackgroundCardiac steatosis and apoptosis are key processes in diabetic cardiomyopathy, but the underlying mechanisms have not been elucidated, leading to a lack of effective therapy. The mineralocorticoid receptor blocker, eplerenone, has demonstrated anti-fibrotic actions in the diabetic heart. However, its effects on the fatty-acid accumulation and apoptotic responses have not been revealed.MethodsNon-hypertensive Zucker Diabetic Fatty (ZDF) rats received eplerenone (25 mg/kg) or vehicle. Zucker Lean (ZL) rats were used as control (n = 10, each group). After 16 weeks, cardiac structure and function was examined, and plasma and hearts were isolated for biochemical and histological approaches. Cultured cardiomyocytes were used for in vitro assays to determine the direct effects of eplerenone on high fatty acid and high glucose exposed cells.ResultsIn contrast to ZL, ZDF rats exhibited hyperglycemia, hyperlipidemia, insulin-resistance, cardiac steatosis and diastolic dysfunction. The ZDF myocardium also showed increased mitochondrial oxidation and apoptosis. Importantly, eplerenone mitigated these events without altering hyperglycemia. In cultured cardiomyocytes, high-concentrations of palmitate stimulated the fatty-acid uptake (in detriment of glucose assimilation), accumulation of lipid metabolites, mitochondrial dysfunction, and apoptosis. Interestingly, fatty-acid uptake, ceramides formation and apoptosis were also significantly ameliorated by eplerenone.ConclusionsBy blocking mineralocorticoid receptors, eplerenone may attenuate cardiac steatosis and apoptosis, and subsequent remodelling and diastolic dysfunction in obese/type-II diabetic rats.

Atorvastatin alleviates experimental diabetic cardiomyopathy by suppressing apoptosis and oxidative stress

“…Hyperglycemia increases the level of free fatty acids (FFA; Falcao-Pires and Leite-Moreira 2012) particularly the saturated FA, palmitate, which causes accumulation of the toxic intermediate, ceramide (Pappachan et al 2013). Cardiomyocyte accumulation of palmitate, ceramide and TG enhances oxidative stress, apoptosis as well as cardiac hypertrophy and dysfunction (Guleria et al 2013;Pappachan et al 2013;Palomer et al 2013;Ramirez et al 2013). This also may account for the pale areas inside cardiomyocytes observed in DCM group in the current study.…”

“…However, their underlying mechanisms are still elusive, (Picatoste et al 2013;Ramirez et al 2013). Cardiomyocyte apoptosis is enhanced by hyperglycemiainduced oxidative stress that activates caspase-3 activation pathways (Cai et al 2006;Zou and Xie 2013;Ouyang et al 2014).…”

Molecular mechanism of lipid-induced cardiac insulin resistance and contractile dysfunction

“…Several studies also documented such role of ceramides in cardiac insulin resistance [34,35]. Ceramide directly activates PKCζ, a member of the atypical PKCs, which phosphorylates and inhibits the membraneattachment of Akt/PKB, thereby inhibiting insulin-stimulated glucose uptake by blocking glucose transporter GLUT4 translocation, as well as glycogen synthesis [36,37].…”

Chronic heart failure: Ca 2+ , catabolism, and catastrophic cell death

“…For instance, there exists evidence that in obesity-induced type 2 diabetes mellitus, increased apoptosis and mitochondrial dysfunction contribute to worsening diastolic dysfunction. Further, eplerenone, a mineralocorticoid antagonist, decreased apoptosis, as evidenced by decreases in caspase-3 activation, TUNEL staining, and nuclear pyknosis [284]. However, the distinction between therapeutically regulating apoptosis in diastolic versus systolic HF is difficult to delineate; there may be beneficial effects on systolic function, as well as diastolic function, such that the salutary effects are multifactorial and difficult to separate definitively.…”