Cannabinoid 1 receptor promotes cardiac dysfunction, oxidative stress, inflammation, and fibrosis in diabetic cardiomyopathy.
Endocannabinoids and cannabinoid 1 (CB(1)) receptors have been implicated in cardiac dysfunction, inflammation, and cell death associated with various forms of shock, heart failure, and atherosclerosis, in addition to their recognized role in the development of various cardiovascular risk factors in obesity/metabolic syndrome and diabetes. In this study, we explored the role of CB(1) receptors 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 increased myocardial endocannabinoid anandamide levels, oxidative/nitrative stress, activation of p38/Jun NH(2)-terminal kinase (JNK) mitogen-activated protein kinases (MAPKs), enhanced inflammation (tumor necrosis factor-α, interleukin-1β, cyclooxygenase 2, intracellular adhesion molecule 1, and vascular cell adhesion molecule 1), increased expression of CB(1), advanced glycation end product (AGE) and angiotensin II type 1 receptors (receptor for advanced glycation end product [RAGE], angiotensin II receptor type 1 [AT(1)R]), p47(phox) NADPH oxidase subunit, β-myosin heavy chain isozyme switch, accumulation of AGE, fibrosis, and decreased expression of sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase (SERCA2a). Pharmacological inhibition or genetic deletion of CB(1) receptors attenuated the diabetes-induced cardiac dysfunction and the above-mentioned pathological alterations. Activation of CB(1) receptors by endocannabinoids may play an important role in the pathogenesis of diabetic cardiomyopathy by facilitating MAPK activation, AT(1)R expression/signaling, AGE accumulation, oxidative/nitrative stress, inflammation, and fibrosis. Conversely, CB(1) receptor inhibition may be beneficial in the treatment of diabetic cardiovascular complications.
Laboratory of Physiological Studies, National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland, USA.
Mohanraj
M
Rajesh
Sándor
S
Bátkai
Malek
M
Kechrid
Partha
P
Mukhopadhyay
Wen-Shin
WS
Lee
Béla
B
Horváth
Eileen
E
Holovac
Resat
R
Cinar
Lucas
L
Liaudet
Ken
K
Mackie
György
G
Haskó
Pál
P
Pacher
D000818:Animals; D017209:Apoptosis; D001095:Arachidonic Acids / Q000032:analysis; D058065:Diabetic Cardiomyopathies / Q000209:etiology* / Q000503:physiopathology; D063388:Endocannabinoids; D005355:Fibrosis; D017127:Glycation End Products, Advanced / Q000032:analysis; D006321:Heart / Q000503:physiopathology*; D007249:Inflammation / Q000209:etiology*; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D018384:Oxidative Stress; D053284:Polyunsaturated Alkamides / Q000032:analysis; D044140:Receptor, Angiotensin, Type 1 / Q000032:analysis; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D016277:Ventricular Function, Left
D001095:Arachidonic Acids; D063388:Endocannabinoids; D017127:Glycation End Products, Advanced; D053284:Polyunsaturated Alkamides; D044140:Receptor, Angiotensin, Type 1; D043884:Receptor, Cannabinoid, CB1; C078814:anandamide