Icariin Ameliorates Diabetic Cardiomyopathy Through Apelin/Sirt3 Signalling to Improve Mitochondrial Dysfunction

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-1a, 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

Elabela may regulate SIRT3‐mediated inhibition of oxidative stress through Foxo3a deacetylation preventing diabetic‐induced myocardial injury

“…The mitochondrial electron transport chain is the main source of ROS, and SIRT3 can enhance mitochondria's ROS coping capacity by multiple factors 26 . Recent studies indicated that the protective effect of Apelin/APJ system may depend on SIRT3 and its downstream factors 27‐29 . A research showed that overexpression of Apelin significantly attenuated high glucose‐induced ROS and improved the expression of SIRT3, while Apelin's protection against high glucose‐induced ROS formation was diminished when SIRT3 was knocked out 19 .…”

“…26 Recent studies indicated that the protective effect of Apelin/APJ system may depend on SIRT3 and its downstream factors. [27][28][29] A research showed that overexpression of Apelin significantly attenuated high glucose-induced ROS and improved the expression of SIRT3, while Apelin's protection against high glucose-induced ROS formation was diminished when SIRT3 was knocked out. 19 Hou et al also demonstrated that SIRT3 is essential for Apelin-induced angiogenesis in post-myocardial infarction of diabetes.…”

“…19 Hou et al also demonstrated that SIRT3 is essential for Apelin-induced angiogenesis in post-myocardial infarction of diabetes. 27 In addition, Apelin/SIRT3 signaling has been demonstrated to improve mitochondrial dysfunction in DCM, 29 and SIRT3 deficiency promotes cardiac dysfunction, due to defective trans-mitochondrial cristae alignment and impaired mitochondrial bioenergetics. 30 In our study, Elabela, the new endogenous agonist of APJ, demonstrated the similar functions in DCM as Apelin.…”

Modified Taohong Siwu Decoction Improved Heart Function After Myocardial Infarction by Inhibiting Inflammatory Factor and Promoting Chemotactic and Pro-Angiogenic Factors

“…As a major component of Epimedium, Icariin attenuated myocardial infarct size and cell apoptosis by activating the PI3K/Akt/eNOS-dependent signal pathways [21]. In addition, Icariin ameliorated diabetic cardiomyopathy by preventing mitochondrial dysfunction through the Apelin/Sirt3 pathway [22]. Notopterygii Rhizoma et Radix has been widely used in clinical prescriptions to disperse cold and eliminate dampness in China.…”

The Potential Properties of Natural Compounds in Cardiac Stem Cell Activation: Their Role in Myocardial Regeneration

“…The cardioprotective properties of icariin and its potential involvement in the modulation of the PI3K/Akt signaling pathway were also observed in different animal models of ischemia-reperfusion injury and cardiomyopathies. Indeed, icariin perfusion before ischemia induction and throughout reperfusion, ameliorates cardiac function improving left ventricular diastolic pressure, coronary flow and reducing infarct size, oxidative stress and cardiomyocyte apoptosis [ 178 , 185 , 186 , 187 ]. Moreover, icariin preserves the injured heart from pathological cardiac remodeling, characterized by hypertrophy and degeneration of CMs and inflammatory infiltration, down-regulating Matrix Metallopeptidases (MMP)-2 and MMP-9, increasing Bcl2 levels and decreasing Bax and caspase 3 [ 187 ].…”