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Retinoic acid receptor-mediated signaling protects cardiomyocytes from hyperglycemia induced apoptosis: role of the renin-angiotensin system.

Abstract

Diabetes mellitus (DM) is a primary risk factor for cardiovascular diseases and heart failure. Activation of the retinoic acid receptor (RAR) and retinoid X receptor (RXR) has an anti-diabetic effect; but, a role in diabetic cardiomyopathy remains unclear. Using neonatal and adult cardiomyocytes, we determined the role of RAR and RXR in hyperglycemia-induced apoptosis and expression of renin-angiotensin system (RAS) components. Decreased nuclear expression of RARα and RXRα, activation of apoptotic signaling and cell apoptosis was observed in high glucose (HG) treated neonatal and adult cardiomyocytes and diabetic hearts in Zucker diabetic fatty (ZDF) rats. HG-induced apoptosis and reactive oxygen species (ROS) generation was prevented by both RAR and RXR agonists. Silencing expression of RARα and RXRα, by small interference RNA, promoted apoptosis under normal conditions and significantly enhanced HG-induced apoptosis, indicating that RARα and RXRα are required in regulating cell apoptotic signaling. Blocking angiotensin type 1 receptor (AT(1) R); but, not AT(2) R, attenuated HG-induced apoptosis and ROS generation. Moreover, HG induced gene expression of angiotensinogen, renin, AT(1) R, and angiotensin II (Ang II) synthesis were inhibited by RARα agonists and promoted by silencing RARα. Activation of RXRα, downregulated the expression of AT(1) R; and RXRα silencing accelerated HG induced expression of angiotensinogen and Ang II synthesis, whereas there was no significant effect on renin gene expression. These results indicate that reduction in the expression of RARα and RXRα has an important role in hyperglycemia mediated apoptosis and expression of RAS components. Activation of RAR/RXR signaling protects cardiomyocytes from hyperglycemia, by reducing oxidative stress and inhibition of the RAS.

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  • Authors+Show Affiliations

    ,

    Division of Molecular Cardiology, Department of Medicine, College of Medicine, Texas A&M Health Science Center, Temple, Texas 76504, USA.

    , , ,

    Source

    Journal of cellular physiology 226:5 2011 May pg 1292-307

    MeSH

    Angiotensin II
    Angiotensin Receptor Antagonists
    Animals
    Animals, Newborn
    Apoptosis
    Blood Glucose
    Cells, Cultured
    Diabetes Mellitus
    Disease Models, Animal
    Dose-Response Relationship, Drug
    Gene Expression Regulation
    Hyperglycemia
    Hypoglycemic Agents
    Male
    Myocytes, Cardiac
    Oxidative Stress
    RNA Interference
    RNA, Messenger
    Rats
    Rats, Sprague-Dawley
    Rats, Zucker
    Reactive Oxygen Species
    Receptor, Angiotensin, Type 1
    Receptors, Retinoic Acid
    Renin-Angiotensin System
    Retinoic Acid Receptor alpha
    Retinoid X Receptor alpha
    Signal Transduction
    Time Factors
    Tretinoin

    Pub Type(s)

    Journal Article
    Research Support, N.I.H., Extramural

    Language

    eng

    PubMed ID

    20945395

    Citation

    Guleria, Rakeshwar S., et al. "Retinoic Acid Receptor-mediated Signaling Protects Cardiomyocytes From Hyperglycemia Induced Apoptosis: Role of the Renin-angiotensin System." Journal of Cellular Physiology, vol. 226, no. 5, 2011, pp. 1292-307.
    Guleria RS, Choudhary R, Tanaka T, et al. Retinoic acid receptor-mediated signaling protects cardiomyocytes from hyperglycemia induced apoptosis: role of the renin-angiotensin system. J Cell Physiol. 2011;226(5):1292-307.
    Guleria, R. S., Choudhary, R., Tanaka, T., Baker, K. M., & Pan, J. (2011). Retinoic acid receptor-mediated signaling protects cardiomyocytes from hyperglycemia induced apoptosis: role of the renin-angiotensin system. Journal of Cellular Physiology, 226(5), pp. 1292-307. doi:10.1002/jcp.22457.
    Guleria RS, et al. Retinoic Acid Receptor-mediated Signaling Protects Cardiomyocytes From Hyperglycemia Induced Apoptosis: Role of the Renin-angiotensin System. J Cell Physiol. 2011;226(5):1292-307. PubMed PMID: 20945395.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Retinoic acid receptor-mediated signaling protects cardiomyocytes from hyperglycemia induced apoptosis: role of the renin-angiotensin system. AU - Guleria,Rakeshwar S, AU - Choudhary,Rashmi, AU - Tanaka,Takemi, AU - Baker,Kenneth M, AU - Pan,Jing, PY - 2010/10/15/entrez PY - 2010/10/15/pubmed PY - 2011/4/16/medline SP - 1292 EP - 307 JF - Journal of cellular physiology JO - J. Cell. Physiol. VL - 226 IS - 5 N2 - Diabetes mellitus (DM) is a primary risk factor for cardiovascular diseases and heart failure. Activation of the retinoic acid receptor (RAR) and retinoid X receptor (RXR) has an anti-diabetic effect; but, a role in diabetic cardiomyopathy remains unclear. Using neonatal and adult cardiomyocytes, we determined the role of RAR and RXR in hyperglycemia-induced apoptosis and expression of renin-angiotensin system (RAS) components. Decreased nuclear expression of RARα and RXRα, activation of apoptotic signaling and cell apoptosis was observed in high glucose (HG) treated neonatal and adult cardiomyocytes and diabetic hearts in Zucker diabetic fatty (ZDF) rats. HG-induced apoptosis and reactive oxygen species (ROS) generation was prevented by both RAR and RXR agonists. Silencing expression of RARα and RXRα, by small interference RNA, promoted apoptosis under normal conditions and significantly enhanced HG-induced apoptosis, indicating that RARα and RXRα are required in regulating cell apoptotic signaling. Blocking angiotensin type 1 receptor (AT(1) R); but, not AT(2) R, attenuated HG-induced apoptosis and ROS generation. Moreover, HG induced gene expression of angiotensinogen, renin, AT(1) R, and angiotensin II (Ang II) synthesis were inhibited by RARα agonists and promoted by silencing RARα. Activation of RXRα, downregulated the expression of AT(1) R; and RXRα silencing accelerated HG induced expression of angiotensinogen and Ang II synthesis, whereas there was no significant effect on renin gene expression. These results indicate that reduction in the expression of RARα and RXRα has an important role in hyperglycemia mediated apoptosis and expression of RAS components. Activation of RAR/RXR signaling protects cardiomyocytes from hyperglycemia, by reducing oxidative stress and inhibition of the RAS. SN - 1097-4652 UR - https://www.unboundmedicine.com/medline/citation/20945395/Retinoic_acid_receptor_mediated_signaling_protects_cardiomyocytes_from_hyperglycemia_induced_apoptosis:_role_of_the_renin_angiotensin_system_ L2 - https://doi.org/10.1002/jcp.22457 DB - PRIME DP - Unbound Medicine ER -