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Eplerenone attenuated cardiac steatosis, apoptosis and diastolic dysfunction in experimental type-II diabetes.

Abstract

BACKGROUND

Cardiac steatosis and apoptosis are key processes in diabetic cardiomyopathy, but the underlying mechanisms have not been elucidated, leading to a lack of effective therapy. The mineralocorticoid receptor blocker, eplerenone, has demonstrated anti-fibrotic actions in the diabetic heart. However, its effects on the fatty-acid accumulation and apoptotic responses have not been revealed.

METHODS

Non-hypertensive Zucker Diabetic Fatty (ZDF) rats received eplerenone (25 mg/kg) or vehicle. Zucker Lean (ZL) rats were used as control (n = 10, each group). After 16 weeks, cardiac structure and function was examined, and plasma and hearts were isolated for biochemical and histological approaches. Cultured cardiomyocytes were used for in vitro assays to determine the direct effects of eplerenone on high fatty acid and high glucose exposed cells.

RESULTS

In contrast to ZL, ZDF rats exhibited hyperglycemia, hyperlipidemia, insulin-resistance, cardiac steatosis and diastolic dysfunction. The ZDF myocardium also showed increased mitochondrial oxidation and apoptosis. Importantly, eplerenone mitigated these events without altering hyperglycemia. In cultured cardiomyocytes, high-concentrations of palmitate stimulated the fatty-acid uptake (in detriment of glucose assimilation), accumulation of lipid metabolites, mitochondrial dysfunction, and apoptosis. Interestingly, fatty-acid uptake, ceramides formation and apoptosis were also significantly ameliorated by eplerenone.

CONCLUSIONS

By blocking mineralocorticoid receptors, eplerenone may attenuate cardiac steatosis and apoptosis, and subsequent remodelling and diastolic dysfunction in obese/type-II diabetic rats.

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  • Authors+Show Affiliations

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    Cardiovascular Pathology laboratory, IIS-Fundación Jiménez Díaz, Autónoma University, Av, Reyes Católicos 2, Madrid 28040 Spain. olorenzo@fjd.es.

    Source

    Cardiovascular diabetology 12: 2013 Nov 21 pg 172

    MeSH

    Animals
    Apoptosis
    Cardiomegaly
    Cell Line
    Diabetes Mellitus, Type 2
    Diabetic Cardiomyopathies
    Diastole
    Disease Models, Animal
    Eplerenone
    Fatty Acids
    Fibrosis
    Glucose
    Hyperlipidemias
    Lipid Metabolism
    Male
    Mineralocorticoid Receptor Antagonists
    Mitochondria, Heart
    Myocardium
    Myocytes, Cardiac
    Rats
    Rats, Zucker
    Spironolactone
    Time Factors
    Ventricular Dysfunction
    Ventricular Function
    Ventricular Remodeling

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    24261558

    Citation

    Ramírez, Elisa, et al. "Eplerenone Attenuated Cardiac Steatosis, Apoptosis and Diastolic Dysfunction in Experimental type-II Diabetes." Cardiovascular Diabetology, vol. 12, 2013, p. 172.
    Ramírez E, Klett-Mingo M, Ares-Carrasco S, et al. Eplerenone attenuated cardiac steatosis, apoptosis and diastolic dysfunction in experimental type-II diabetes. Cardiovasc Diabetol. 2013;12:172.
    Ramírez, E., Klett-Mingo, M., Ares-Carrasco, S., Picatoste, B., Ferrarini, A., Rupérez, F. J., ... Lorenzo, Ó. (2013). Eplerenone attenuated cardiac steatosis, apoptosis and diastolic dysfunction in experimental type-II diabetes. Cardiovascular Diabetology, 12, p. 172. doi:10.1186/1475-2840-12-172.
    Ramírez E, et al. Eplerenone Attenuated Cardiac Steatosis, Apoptosis and Diastolic Dysfunction in Experimental type-II Diabetes. Cardiovasc Diabetol. 2013 Nov 21;12:172. PubMed PMID: 24261558.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Eplerenone attenuated cardiac steatosis, apoptosis and diastolic dysfunction in experimental type-II diabetes. AU - Ramírez,Elisa, AU - Klett-Mingo,Mercedes, AU - Ares-Carrasco,Sara, AU - Picatoste,Belén, AU - Ferrarini,Alessia, AU - Rupérez,Francisco J, AU - Caro-Vadillo,Alicia, AU - Barbas,Coral, AU - Egido,Jesús, AU - Tuñón,José, AU - Lorenzo,Óscar, Y1 - 2013/11/21/ PY - 2013/07/30/received PY - 2013/11/09/accepted PY - 2013/11/23/entrez PY - 2013/11/23/pubmed PY - 2014/5/8/medline SP - 172 EP - 172 JF - Cardiovascular diabetology JO - Cardiovasc Diabetol VL - 12 N2 - BACKGROUND: Cardiac steatosis and apoptosis are key processes in diabetic cardiomyopathy, but the underlying mechanisms have not been elucidated, leading to a lack of effective therapy. The mineralocorticoid receptor blocker, eplerenone, has demonstrated anti-fibrotic actions in the diabetic heart. However, its effects on the fatty-acid accumulation and apoptotic responses have not been revealed. METHODS: Non-hypertensive Zucker Diabetic Fatty (ZDF) rats received eplerenone (25 mg/kg) or vehicle. Zucker Lean (ZL) rats were used as control (n = 10, each group). After 16 weeks, cardiac structure and function was examined, and plasma and hearts were isolated for biochemical and histological approaches. Cultured cardiomyocytes were used for in vitro assays to determine the direct effects of eplerenone on high fatty acid and high glucose exposed cells. RESULTS: In contrast to ZL, ZDF rats exhibited hyperglycemia, hyperlipidemia, insulin-resistance, cardiac steatosis and diastolic dysfunction. The ZDF myocardium also showed increased mitochondrial oxidation and apoptosis. Importantly, eplerenone mitigated these events without altering hyperglycemia. In cultured cardiomyocytes, high-concentrations of palmitate stimulated the fatty-acid uptake (in detriment of glucose assimilation), accumulation of lipid metabolites, mitochondrial dysfunction, and apoptosis. Interestingly, fatty-acid uptake, ceramides formation and apoptosis were also significantly ameliorated by eplerenone. CONCLUSIONS: By blocking mineralocorticoid receptors, eplerenone may attenuate cardiac steatosis and apoptosis, and subsequent remodelling and diastolic dysfunction in obese/type-II diabetic rats. SN - 1475-2840 UR - https://www.unboundmedicine.com/medline/citation/24261558/Eplerenone_attenuated_cardiac_steatosis_apoptosis_and_diastolic_dysfunction_in_experimental_type_II_diabetes_ L2 - https://cardiab.biomedcentral.com/articles/10.1186/1475-2840-12-172 DB - PRIME DP - Unbound Medicine ER -