Endocrine Abstracts

β-Caryophyllene, a dietary CB2 receptor selective cannabinoid mitigates myocardial fibrosis in a mice model of diabetic cardiomyopathy

Background and aim: Diabetic cardiomyopathy (DCM), a cardiac complication in diabetes is characterized by abnormal cardiac function accompanied with myocardial fibrosis. In recent years, the cannabinoid type 2 receptors (CB2) emerged as a crucial therapeutic target for diabetes and its complications. The downregulation of CB2 receptors has been documented in various cardiovascular diseases and diabetes, that supports the concepts that activation of CB2 receptors may protect against diabetic cardiomyopathy. The present study was designed to investigate the effect of a selective CB2 receptor agonist β-Caryophyllene (BCP), a dietary natural cannabinoid compound and chemically a bicyclic sesquiterpene on myocardial fibrosis in DCM mice.

Methods: Experimental DCM was developed in Male C57/B6 mice by feeding a high-fat diet for 4 weeks followed by a low dose of streptozotocin (100 mg/kg) injection. Both DCM and control mice were then treated with or without BCP (50 mg/kg, orally) for 12 weeks by continuous feeding of a high fat or normal diet. At the end of this period, hemodynamic parameters (systolic blood pressure, diastolic blood pressure, mean arterial pressure, heart rate), and heart weight/body weight were evaluated, fasting blood glucose, oral glucose tolerance test, insulin level, lipid parameters (triglyceride, total cholesterol, low-density lipoprotein, very-low-density lipoprotein, high-density lipoprotein), and lactate dehydrogenase in serum were detected. Hematoxylin-eosin and picrosirius red were employed to determine heart morphological changes and cardiac fibrosis, respectively. Immunohistochemistry of collagen I and III and western blotting were taken to determine the expression levels of cardiac-fibrosis markers (TGF-β, SMAD, α-SMA).

Results: DCM mice exhibited hyperglycemia, insulin resistance, hyperlipidemia, hemodynamic abnormalities, significantly increased serum lactate dehydrogenase along with increased myocardial fibrosis, and hypertrophy. Oral administration of BCP significantly decreased the levels of blood glucose, serum lipids, while increased serum insulin level with improving the insulin resistance. Additionally, the myocardial enzyme (lactate dehydrogenase) was significantly decreased. Furthermore, BCP significantly improved hemodynamic changes and attenuated the abnormal morphologic change in DCM hearts. Moreover, BCP treatment decreased the expression of TGF-β, SMAD, α-SMA and reduced collagen deposition in the heart of DCM mice. Most importantly, pre-administration of the CB2 receptor antagonist AM630, abrogated the protective effects of BCP in DCM mice.

Conclusion: These results suggest that activation of CB2 receptors by BCP alleviated diabetic cardiomyopathy by attenuating hyperglycemia/hyperlipidemia-induced cardiac fibrosis and remodeling via TGF-β/SMAD signaling pathway.