Cannabinoid 1 receptor promotes cardiac dysfunction, oxidative stress, inflammation, and fibrosis in diabetic cardiomyopathy

Mohanraj Rajesh, Sándor Bátkai, Malek Kechrid, Partha Mukhopadhyay, Wen Shin Lee, Béla Horváth, Eileen Holovac, Resat Cinar, Lucas Liaudet, Ken Mackie, G. Haskó, Pál Pacher

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Abstract

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 1R]), 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 1R 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.

Original languageEnglish
Pages (from-to)716-727
Number of pages12
JournalDiabetes
Volume61
Issue number3
DOIs
Publication statusPublished - Mar 2012

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Diabetic Cardiomyopathies
Cannabinoid Receptors
Oxidative Stress
Fibrosis
Endocannabinoids
Advanced Glycosylation End Products
Inflammation
Angiotensin Type 1 Receptor
Cell Death
MAP Kinase Kinase 2
Sarcoplasmic Reticulum Calcium-Transporting ATPases
Vascular Cell Adhesion Molecule-1
Myosin Heavy Chains
Cannabinoids
NADPH Oxidase
Diabetes Complications
Cyclooxygenase 2
Mitogen-Activated Protein Kinases
Interleukin-1
Endoplasmic Reticulum

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Rajesh, M., Bátkai, S., Kechrid, M., Mukhopadhyay, P., Lee, W. S., Horváth, B., ... Pacher, P. (2012). Cannabinoid 1 receptor promotes cardiac dysfunction, oxidative stress, inflammation, and fibrosis in diabetic cardiomyopathy. Diabetes, 61(3), 716-727. https://doi.org/10.2337/db11-0477

Cannabinoid 1 receptor promotes cardiac dysfunction, oxidative stress, inflammation, and fibrosis in diabetic cardiomyopathy. / Rajesh, Mohanraj; Bátkai, Sándor; Kechrid, Malek; Mukhopadhyay, Partha; Lee, Wen Shin; Horváth, Béla; Holovac, Eileen; Cinar, Resat; Liaudet, Lucas; Mackie, Ken; Haskó, G.; Pacher, Pál.

In: Diabetes, Vol. 61, No. 3, 03.2012, p. 716-727.

Research output: Contribution to journalArticle

Rajesh, M, Bátkai, S, Kechrid, M, Mukhopadhyay, P, Lee, WS, Horváth, B, Holovac, E, Cinar, R, Liaudet, L, Mackie, K, Haskó, G & Pacher, P 2012, 'Cannabinoid 1 receptor promotes cardiac dysfunction, oxidative stress, inflammation, and fibrosis in diabetic cardiomyopathy', Diabetes, vol. 61, no. 3, pp. 716-727. https://doi.org/10.2337/db11-0477
Rajesh, Mohanraj ; Bátkai, Sándor ; Kechrid, Malek ; Mukhopadhyay, Partha ; Lee, Wen Shin ; Horváth, Béla ; Holovac, Eileen ; Cinar, Resat ; Liaudet, Lucas ; Mackie, Ken ; Haskó, G. ; Pacher, Pál. / Cannabinoid 1 receptor promotes cardiac dysfunction, oxidative stress, inflammation, and fibrosis in diabetic cardiomyopathy. In: Diabetes. 2012 ; Vol. 61, No. 3. pp. 716-727.
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