The cannabinoid receptor type 2 promotes cardiac myocyte and fibroblast survival and protects against ischemia/reperfusion-induced cardiomyopathy.
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 H(2)O(2)-induced death than WT cells, whereas 1 microM JWH133 triggered survival effects. Furthermore, H(2)O(2)-induced myofibroblast activation was increased in CB2(-/-) fibroblasts but decreased in 1 microM 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
Nicole
N
INSERM, Unité 955, Créteil, France.
Wan
Jinghong
J
Souktani
Richard
R
Escoubet
Brigitte
B
Perier
Magali
M
Caramelle
Philippe
P
Manin
Sylvie
S
Deveaux
Vanessa
V
Bourin
Marie-Claude
MC
Zimmer
Andreas
A
Lotersztajn
Sophie
S
Pecker
Françoise
F
Pavoine
Catherine
C
D000818:Animals; D009202:Cardiomyopathies / Q000209:etiology*; D002470:Cell Survival; D005347:Fibroblasts / Q000166:cytology*; D006861:Hydrogen Peroxide; D051379:Mice; D018345:Mice, Knockout; D015428:Myocardial Reperfusion Injury / Q000150:complications*; D009206:Myocardium / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000166:cytology*; D020011:Protective Agents; D043885:Receptor, Cannabinoid, CB2 / Q000172:deficiency / Q000502:physiology*; D018487:Ventricular Dysfunction, Left / Q000209:etiology
D020011:Protective Agents; D043885:Receptor, Cannabinoid, CB2; D006861:Hydrogen Peroxide