cannabinoid receptor type 2 promotes cardiac myocyte and fibroblast survival and protects against ischemia/reperfusion-induced cardiomyopathy

• Published in: The FASEB journal Vol. 23; no. 7; pp. 2120 - 2130
• Main Authors: Defer, Nicole, Wan, Jinghong, Souktani, Richard, Escoubet, Brigitte, Perier, Magali, Caramelle, Philippe, Manin, Sylvie, Deveaux, Vanessa, Bourin, Marie-Claude, Zimmer, Andreas, Lotersztajn, Sophie, Pecker, Françoise, Pavoine, Catherine
• Format: Journal Article
• Language: English
• Published: United States The Federation of American Societies for Experimental Biology 01.07.2009
• Subjects: Animals; Cardiomyopathies - etiology; Cell Survival; Fibroblasts - cytology; Hydrogen Peroxide; Mice; Mice, Knockout; Myocardial Reperfusion Injury - complications; Myocardium - pathology; Myocytes, Cardiac - cytology; Protective Agents; Receptor, Cannabinoid, CB2 - deficiency; Receptor, Cannabinoid, CB2 - physiology; Ventricular Dysfunction, Left - etiology
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.09-129478

Post-myocardial infarction (MI) heart failure is a major public health problem in Western countries and results from ischemia/reperfusion (IR)-induced cell death, remodeling, and contractile dysfunction. Ex vivo studies have demonstrated the cardioprotective anti-inflammatory effect of the cannabinoid type 2 (CB2) receptor agonists within hours after IR. Herein, we evaluated the in vivo effect of CB2 receptors on IR-induced cell death, fibrosis, and cardiac dysfunction and investigated the target role of cardiac myocytes and fibroblasts. The infarct size was increased 24 h after IR in CB2⁻/⁻ vs. wild-type (WT) hearts and decreased when WT hearts were injected with the CB2 agonist JWH133 (3 mg/kg) at reperfusion. Compared with WT hearts, CB2⁻/⁻ hearts showed widespread injury 3 d after IR, with enhanced apoptosis and remodeling affecting the remote myocardium. Finally, CB2⁻/⁻ hearts exhibited exacerbated fibrosis, associated with left ventricular dysfunction 4 wk after IR, whereas their WT counterparts recovered normal function. Cardiac myocytes and fibroblasts isolated from CB2⁻/⁻ hearts displayed a higher H₂O₂-induced death than WT cells, whereas 1 μM JWH133 triggered survival effects. Furthermore, H₂O₂-induced myofibroblast activation was increased in CB2⁻/⁻ fibroblasts but decreased in 1 μM JWH133-treated WT fibroblasts, compared with that in WT cells. Therefore, CB2 receptor activation may protect against post-IR heart failure through direct inhibition of cardiac myocyte and fibroblast death and prevention of myofibroblast activation.--Defer, N., Wan, J., Souktani, R., Escoubet, B., Perier, M., Caramelle, P., Manin, S., Deveaux, V., Bourin, M.-C., Zimmer, A., Lotersztajn, S., Pecker, F., Pavoine, C. The cannabinoid receptor type 2 promotes cardiac myocyte and fibroblast survival and protects against ischemia/reperfusion-induced cardiomyopathy.