Activating Cannabinoid Receptor 2 Protects Against Diabetic Cardiomyopathy Through Autophagy Induction

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.

Activation of cannabinoid receptor type 2-induced osteogenic differentiation involves autophagy induction and p62-mediated Nrf2 deactivation

“…In addition to initiating autophagy, we also found that both CNR2 agonists suppressed mTOR signaling transduction. The inhibitory effects of HU308 on mTOR pathway in cardiomyocytes observed by Wu et al [15] indirectly supported our current findings. Furthermore, CNR2 ligands' effects on mTOR associated-autophagy were attenuated in CNR2-silenced cells.…”

“…Forty-eight hours later, cells were further treated with 50 nM HU308 or 10 μM JWH133 for 12 h, and then harvested for western blotting analysis degradation of p62 indicates an effective autophagic flux in differentiated hFOB 1.19 cells. On the basis of previous studies showing that CNR2 agonist HU308 augmented cellular autophagy [14,15], we propose that CNR2 activation contributes to autophagy initiation in the differentiated osteoblasts. To valid this hypothesis, we treated hFOB 1.19 cells with increasing doses of CNR2 ligands HU308 and JWH133, and found that the autophagic flux was gradually enhanced.…”

“…Nevertheless, several previous lines of evidence imply that CNR2 agonists can regulate autophagy flux. In macrophages and cardiomyocytes, HU308 was found to enhance cellular autophagy [14,15]. We therefore proposed that activation of CNR2 signaling may enhance the osteogenic differentiation by provoking autophagy.…”

A Guide to Targeting the Endocannabinoid System in Drug Design

“…The CB2 activation enhances insulin release, decreases pro-inflammatory cytokines' levels, and attenuates oxidative stress [234]. In addition, activation of CB2 by HU308 (3 mg/kg/day) exerted a cardioprotective effect in diabetic cardiomyopathy in mice [235].…”

N‑linoleyltyrosine protects PC12 cells against oxidative damage via autophagy: Possible�involvement of CB1 receptor regulation

“…It has been demonstrated that as the ligand for the cannabinoid type 1 (cB1) and 2 (cB2) receptors, anandamide (AEA) exerts neuroprotective effects by inhibiting oxidative stress and free radical formation (8). Additionally, cannabinoids and activating cannabinoid receptors induce autophagy in cardiovascular disease (9)(10)(11). However, the rapid metabolic inactivation of AEA in vivo has limited its further application (12); thus, the development of novel AEA analogs is of considerable importance.…”