Activating Cannabinoid Receptor 2 Protects Against Diabetic Cardiomyopathy Through Autophagy Induction.

Aiping Wu,Rui Zhang,Wan Xia,Jian Lin,Pengfei Hu

doi:10.3389/fphar.2018.01292

Abstract

Cannabinoid receptor 2 (CB2) has been reported to produce a cardio-protective effect in cardiovascular diseases such as myocardial infarction. Here in this study, we investigated the role of CB2 in diabetic cardiomyopathy (DCM) and its underlying mechanisms. HU308 was used for the selective activation of CB2. Bafilomycin A1 was used for the blockade of autophagy and compound C was used to inhibit AMPK signaling. An streptozotocin (STZ)-induced mice model and high glucose (HG)-challenged cardiomyocytes were applied for study. Cardiac function was detected by echocardiography and Western blot for the detection of autophagy-related and its signaling-related proteins. Transmission electron microscopy was used for the analysis of autophagosome number. Cell viability was detected by Cell Counting Kit-8 (CCK-8) and lactate dehydrogenase (LDH) release assays. We found that activating CB2 by HU308 improved cardiac function in DCM as well as cell viability in cardiomyocytes under HG challenge, while the administration of bafilomycin A1 attenuated the protective effects. HU308 enhanced the level of autophagy in the heart tissues from DCM mice as well as cardiomyocytes under HG challenge. HU308 triggered the AMPK-mTOR-p70S6K signaling pathway, while the administration of compound C attenuated the cardio-protective effect of HU308 in cardiomyocytes under HG challenge. In conclusion, we initially demonstrated that activating CB2 produced a cardio-protective effect in DCM as well as cardiomyocytes under HG challenge through inducing the AMPK-mTOR-p70S6K signaling-mediated autophagy.

Highlights

Diabetic cardiomyopathy (DCM) refers to a disorder of the heart muscle in people with diabetes in the absence of coronary artery disease or hypertension, serving as a major cause of heart failure in diabetic patients (Picano, 2003; Avogaro et al, 2004; Wang et al, 2016)
We found that compared with the normal group, the occurrence of DCM deteriorated the damage of cardiac function in ejection fraction (EF) (%), fractional shortening (FS) (%), left ventricular end-systolic diameter (LVESD) and left ventricular end-diastolic diameter (LVEDD), while the administration of HU308 significantly attenuated those effects of DCM (Figures 1A–E)
Since autophagy has been reported to play an alleviative role in DCM, we detected the effect of activating Cannabinoid receptor 2 (CB2) on autophagy process in heart issues on the occurrence of DCM

Summary

Introduction

Diabetic cardiomyopathy (DCM) refers to a disorder of the heart muscle in people with diabetes in the absence of coronary artery disease or hypertension, serving as a major cause of heart failure in diabetic patients (Picano, 2003; Avogaro et al, 2004; Wang et al, 2016). Since diabetic patients have been reported to have higher risk than those without diabetes in heart failure (twofold higher in male and fivefold higher in female), it is urgent to gain knowledge and manage the pathogenesis and progression of DCM (Preis et al, 2009; Xiao et al, 2018). Activating CB2 has been reported to produce a cardio-protective effect in myocardial ischemia as well as other cardiovascular diseases like atherosclerosis (Moris et al, 2015; Maslov et al, 2016; Maslov and Karpov, 2017). Whether activating CB2 protects against DCM has not been elucidated

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