Abstract
Myocardial contractile dysfunction in diabetic cardiomyocytes is a significant promoter of heart failure. Herein, we investigated the effect of icariin, a flavonoid monomer isolated from Epimedium, on diabetic cardiomyopathy (DCM) and explored the mechanisms underlying its unique pharmacological cardioprotective functions. High glucose (HG) conditions were simulated in vitro using cardiomyocytes isolated from neonatal C57 mice, while DCM was stimulated in vivo in db/db mice. Mice and cardiomyocytes were treated with icariin, with or without overexpression or silencing of Apelin and Sirt3 via transfection with adenoviral vectors (Ad-RNA) and specific small hairpin RNAs (Ad-sh-RNA), respectively. Icariin markedly improved mitochondrial function both in vivo and in vitro, as evidenced by an increased level of mitochondrial-related proteins via western blot analysis (PGC-1α, Mfn2, and Cyt-b) and an increased mitochondrial membrane potential, as observed via JC-1 staining. Further, icariin treatment decreased cardiac fibrogenesis (Masson staining), and inhibited apoptosis (TUNEL staining). Together, these changes improved cardiac function, according to multiple transthoracic echocardiography parameters, including LVEF, LVSF, LVESD, and LVEDD. Moreover, icariin significantly activated Apelin and Sirt3, which were inhibited by HG and DCM. Importantly, when Ad-sh-Apelin and Ad-sh-Sirt3 were transfected in cardiomyocytes or injected into the heart of db/db mice, the cardioprotective effects of icariin were abolished and mitochondrial homeostasis was disrupted. Further, it was postulated that since Ad-Apelin induced different results following increased Sirt3 expression, icariin may have attenuated DCM development by preventing mitochondrial dysfunction through the Apelin/Sirt3 pathway. Hence, protection against mitochondrial dysfunction using icariin may prove to be a promising therapeutic strategy against DCM in diabetes.
Highlights
In the present decade, the prevalence of diabetes and its associated complications have been steadily increasing, within developing countries
Expression of Apelin and Sirt3 was observed in the high glucose (HG) group (Figures 2G, H, P < 0.05), while icariin treatment dramatically alleviated the reduction in Apelin and Sirt3 expression, as previously reported, Sirt1 expression was consistent with this change
We systematically demonstrated that the cardioprotective effect of icariin against diabetic cardiomyopathy (DCM) relies on preventing mitochondrial dysfunction through the activation of Apelin/Sirt3 signaling
Summary
The prevalence of diabetes and its associated complications have been steadily increasing, within developing countries. Despite the introduction of antidiabetic drugs in the United States (US), deaths due to heart failure in diabetic patients have not declined from 19852015 (Cheng et al, 2018). Mitochondria are critical organelles for energy production via oxidative phosphorylation, a reaction that is conjugated with the production of reactive oxygen species (ROS), which either induces diverse molecular signals or cell persecution and death in cardiomyocytes (Zhou and Tian, 2018). Recent studies have revealed that high glucose (HG) concentrations induce a loss of mitochondrial networks and increased reactive ROS in cardiomyocytes (Evangelista et al, 2019). Increasing evidence demonstrates that mitochondrial dysfunction contributes to the pathogenesis of DCM (Schilling, 2015; Verma et al, 2017; Zhou and Tian, 2018; Mahalakshmi and Kurian, 2019). The mitochondrion-targeted methylglyoxal- sequestering compound MitoGamide exhibits cardioprotective effects in an experimental model of DCM (Tate et al, 2019), thereby suggesting that the alleviation of mitochondrial dysfunction may provide a novel therapeutic approach for reversing the development of DCM
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