Cannabinoid 1 Receptor Promotes Cardiac Dysfunction, Oxidative Stress, Inflammation, and Fibrosis in Diabetic Cardiomyopathy
- Mohanraj Rajesh1,
- Sándor Bátkai1,2,
- Malek Kechrid1,
- Partha Mukhopadhyay1,
- Wen-Shin Lee1,
- Béla Horváth1,
- Eileen Holovac1,
- Resat Cinar1,
- Lucas Liaudet3,
- Ken Mackie4,
- György Haskó5 and
- Pál Pacher1⇓
- 1Laboratory of Physiological Studies, National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland
- 2Institute for Molecular and Translational Therapeutic Strategies, Hannover Medical School, Hannover, Germany;
- 3Department of Intensive Care Medicine, University Hospital, Lausanne, Switzerland
- 4Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana
- 5Department of Surgery, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, New Jersey
- Corresponding author: Pál Pacher, .
M.R. and S.B. contributed equally to this work.
Endocannabinoids and cannabinoid 1 (CB1) 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 CB1 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 NH2-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 CB1, advanced glycation end product (AGE) and angiotensin II type 1 receptors (receptor for advanced glycation end product [RAGE], angiotensin II receptor type 1 [AT1R]), p47(phox) NADPH oxidase subunit, β-myosin heavy chain isozyme switch, accumulation of AGE, fibrosis, and decreased expression of sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA2a). Pharmacological inhibition or genetic deletion of CB1 receptors attenuated the diabetes-induced cardiac dysfunction and the above-mentioned pathological alterations. Activation of CB1 receptors by endocannabinoids may play an important role in the pathogenesis of diabetic cardiomyopathy by facilitating MAPK activation, AT1R expression/signaling, AGE accumulation, oxidative/nitrative stress, inflammation, and fibrosis. Conversely, CB1 receptor inhibition may be beneficial in the treatment of diabetic cardiovascular complications.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db11-0477/-/DC1.
- Received April 8, 2011.
- Accepted December 6, 2011.
- © 2012 by the American Diabetes Association.
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