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

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(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.

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  • Authors+Show Affiliations

    ,

    Laboratory of Physiological Studies, National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland, USA.

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    Source

    Diabetes 61:3 2012 Mar pg 716-27

    MeSH

    Animals
    Apoptosis
    Arachidonic Acids
    Diabetic Cardiomyopathies
    Endocannabinoids
    Fibrosis
    Glycation End Products, Advanced
    Heart
    Inflammation
    MAP Kinase Signaling System
    Male
    Mice
    Mice, Inbred C57BL
    Myocardium
    Oxidative Stress
    Polyunsaturated Alkamides
    Receptor, Angiotensin, Type 1
    Receptor, Cannabinoid, CB1
    Ventricular Function, Left

    Pub Type(s)

    Journal Article
    Research Support, N.I.H., Intramural
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    22315315

    Citation

    Rajesh, Mohanraj, et al. "Cannabinoid 1 Receptor Promotes Cardiac Dysfunction, Oxidative Stress, Inflammation, and Fibrosis in Diabetic Cardiomyopathy." Diabetes, vol. 61, no. 3, 2012, pp. 716-27.
    Rajesh M, Bátkai S, Kechrid M, et al. Cannabinoid 1 receptor promotes cardiac dysfunction, oxidative stress, inflammation, and fibrosis in diabetic cardiomyopathy. Diabetes. 2012;61(3):716-27.
    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), pp. 716-27. doi:10.2337/db11-0477.
    Rajesh M, et al. Cannabinoid 1 Receptor Promotes Cardiac Dysfunction, Oxidative Stress, Inflammation, and Fibrosis in Diabetic Cardiomyopathy. Diabetes. 2012;61(3):716-27. PubMed PMID: 22315315.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Cannabinoid 1 receptor promotes cardiac dysfunction, oxidative stress, inflammation, and fibrosis in diabetic cardiomyopathy. AU - Rajesh,Mohanraj, AU - Bátkai,Sándor, AU - Kechrid,Malek, AU - Mukhopadhyay,Partha, AU - Lee,Wen-Shin, AU - Horváth,Béla, AU - Holovac,Eileen, AU - Cinar,Resat, AU - Liaudet,Lucas, AU - Mackie,Ken, AU - Haskó,György, AU - Pacher,Pál, Y1 - 2012/02/07/ PY - 2012/2/9/entrez PY - 2012/2/9/pubmed PY - 2012/4/11/medline SP - 716 EP - 27 JF - Diabetes JO - Diabetes VL - 61 IS - 3 N2 - 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. SN - 1939-327X UR - https://www.unboundmedicine.com/medline/citation/22315315/Cannabinoid_1_receptor_promotes_cardiac_dysfunction_oxidative_stress_inflammation_and_fibrosis_in_diabetic_cardiomyopathy_ L2 - http://diabetes.diabetesjournals.org/cgi/pmidlookup?view=long&pmid=22315315 DB - PRIME DP - Unbound Medicine ER -