Diabetes mellitus promotes accelerated cardiovascular aging and inflammation, which
in turn facilitate the development of cardiomyopathy/heart failure. High glucose-induced
oxidative/nitrative stress, activation of various pro-inflammatory, and cell death
pathways are critical in the initiation and progression of the changes culminating
in diabetic cardiomyopathy. Cannabinoid 2 receptor (CB2R) activation in inflammatory
cells and activated endothelium attenuates the pathological changes associated with
atherosclerosis, myocardial infarction, stroke, and hepatic cardiomyopathy. In this
study, we explored the role of CB2R signaling in myocardial dysfunction, oxidative/nitrative
stress, inflammation, cell death, remodeling, and fibrosis associated with diabetic
cardiomyopathy in type 1 diabetic mice. Control human heart left ventricles and atrial
appendages, similarly to mouse hearts, had negligible CB2R expression determine by
RNA sequencing or real-time RT-PCR. Diabetic cardiomyopathy was characterized by impaired
diastolic and systolic cardiac function, enhanced myocardial CB2R expression, oxidative/nitrative
stress, and pro-inflammatory response (tumor necrosis factor-α, interleukin-1β, intracellular
adhesion molecule 1, macrophage inflammatory protein-1, monocyte chemoattractant protein-1),
macrophage infiltration, fibrosis, and cell death. Pharmacological activation of CB2R
with a selective agonist attenuated diabetes-induced inflammation, oxidative/nitrative
stress, fibrosis and cell demise, and consequent cardiac dysfunction without affecting
hyperglycemia. In contrast, genetic deletion of CB2R aggravated myocardial pathology.
Thus, selective activation of CB2R ameliorates diabetes-induced myocardial tissue
injury and preserves the functional contractile capacity of the myocardium in the
diabetic milieu. This is particularly encouraging, since unlike CB1R agonists, CB2R
agonists do not elicit psychoactive activity and cardiovascular side effects and are
potential clinical candidates in the treatment of diabetic cardiovascular and other
complications.
