CB1 cannabinoid receptor deficiency promotes cardiac remodeling induced by pressure overload in mice.
BACKGROUND
The endocannabinoid system is known to play a role in regulating myocardial contractility, but the influence of cannabinoid receptor 1 (CB1) deficiency on chronic heart failure (CHF) remains unclear. In this study we attempted to investigate the effect of CB1 deficiency on CHF induced by pressure overload and the possible mechanisms involved.


RESULTS
A CHF model was created by transverse aortic constriction (TAC) in both CB1 knockout mice and wild-type mice. CB1 knockout mice showed a marked increase of mortality due to CHF from 4 to 8 weeks after TAC (p=0.021). Five weeks after TAC, in contrast to wild-type mice, CB1 knockout mice had a higher left ventricular (LV) end-diastolic pressure, lower rate of LV pressure change (± dp/dt max), lower LV contractility index, and a larger heart weight to body weight ratio and lung weight to body weight ratio compared with wild-type mice (all p<0.05-0.001). Phosphorylation of the epidermal growth factor receptor (EGFR) and mitogen-activated protein kinases (P38 and ERK) was higher in CB1 knockout mice than that in wild-type mice. In cultured neonatal rat cardiomyocytes, a CB1 agonist reduced cAMP production stimulated by isoproterenol or forskolin, and suppressed phosphorylation of the EGFR, P38, and ERK, while the inhibitory effect of a CB1 agonist on EGFR phosphorylation was abrogated by CB1 knockdown.


CONCLUSIONS
These findings indicate that cannabinoid receptor 1 inactivation promotes cardiac remodeling by enhancing the activity of the epidermal growth factor receptor and mitogen-activated protein kinases.
Department of Cardiology, and Organ Failure Key Laboratory of Ministry of Education, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou 510515, China. Liao18@msn.com
Yulin
Y
Liao
Jianping
J
Bin
Tao
T
Luo
Hui
H
Zhao
Catherine
C
Ledent
Masanori
M
Asakura
Dingli
D
Xu
Seiji
S
Takashima
Masafumi
M
Kitakaze
D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D066246:ErbB Receptors / Q000378:metabolism*; D006333:Heart Failure / Q000378:metabolism* / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D010766:Phosphorylation / Q000502:physiology; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000172:deficiency*; D020257:Ventricular Remodeling / Q000502:physiology*
D043884:Receptor, Cannabinoid, CB1; C541485:EGFR protein, mouse; D066246:ErbB Receptors