Cannabinoid 1 Receptor Promotes Cardiac Dysfunction, Oxidative Stress, Inflammation, and Fibrosis in Diabetic Cardiomyopathy

Abstract

Endocannabinoids and cannabinoid (CB)1 receptors have been implicated in cardiac dysfunction, inflammation, and cell death associated with various forms of shock, heart failure, and atherosclerosis. We explored the role of CB1 receptors in cardiac dysfunction, inflammation and cell death using a mouse model of type 1 diabetic cardiomyopathy. Diabetic cardiomyopathy was characterized by increased myocardial endocannabinoid anandamide levels, oxidative/nitrative stress, activation of p38/Jun kinase, mitogen‐activated protein kinases, enhanced inflammation, increased expression of CB1, advanced glycation end product and angiotensin II type 1 receptors[AT(1)R], p47(phox), β‐myosin heavy chain isozyme switch, accumulation of AGE, fibrosis, and decreased expression of sarcoplasmic/endoplasmic reticulum Ca(2+)‐ATPase. Pharmacological inhibition or genetic deletion of CB1 receptors attenuated the diabetes‐induced cardiac dysfunction and the above‐mentioned pathological alterations. Activation of CB1 receptors by endocannabinoids may play an important role in the pathogenesis of diabetic cardiomyopathy by facilitating MAPK activation, AT(1)R expression/signaling, AGE accumulation, oxidative/nitrative stress, inflammation, and fibrosis. Conversely, CB1 receptor inhibition may be beneficial in the treatment of diabetic cardiovascular complications.