NIH Research Festival
Cardiomyopathy and heart failure are among the most serious complications of diabetes. Recent studies have suggested a very important role of chronic inflammatory processes in diabetic cardiovascular complications. Accumulating evidence also suggests that the novel G-protein coupled cannabinoid receptor 2 (CB2) signaling in inflammatory, endothelial cells, cardiomyocytes and fibroblasts may exert beneficial anti-inflammatory and antifibrotic effects. Thus, we aimed to investigate the role of CB2 signaling in myocardial dysfunction, inflammation, oxidative/nitrative stress, cell death, and interrelated signaling pathways, using a mouse model of type 1 diabetic cardiomyopathy. Diabetic cardiomyopathy was characterized by impaired myocardial contractile function, resulting from increased myocardial oxidative/nitrative stress (3-nitrotyrosine, 4-hydroxy-nonenal, gp22phox, gp67phox, gp91phox), enhanced inflammation (tumor necrosis factor-α, interleukin-1β, intracellular adhesion molecule 1), increased fibrosis (picrosirius staining, collagen-1, CTGF, fibronectin, and TGF- β expression), and activation of cell death cascades (caspase-3 and -7, PARP) . Pharmacological activation of CB2 receptors with a selective agonist attenuated diabetes-induced cardiac dysfunction and the above-mentioned pathological alterations, while genetic inhibition (in CB2 knock-out mice) resulted in aggravation of myocardial pathology. We conclude that selective activation of CB2R can ameliorate diabetes-induced myocardial tissue injury and preserve the functional contractile capacity of the myocardium in the diabetic milieu. This is particularly encouraging, since unlike cannabinoid 1 receptor (CB1) agonists, CB2 agonists do not elicit psychoactive properties, and therefore are potential novel clinical candidates in the treatment of diabetic cardiovascular complications.
Scientific Focus Area: Molecular Pharmacology
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