دورية أكاديمية
Aldehyde Dehydrogenase 2 Activator Augments the Beneficial Effects of Empagliflozin in Mice with Diabetes-Associated HFpEF
العنوان: | Aldehyde Dehydrogenase 2 Activator Augments the Beneficial Effects of Empagliflozin in Mice with Diabetes-Associated HFpEF |
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المؤلفون: | Guodong Pan, Bipradas Roy, Shailendra Giri, David E. Lanfear, Rajarajan A. Thandavarayan, Ashrith Guha, Pablo A. Ortiz, Suresh Selvaraj Palaniyandi |
المصدر: | International Journal of Molecular Sciences, Vol 23, Iss 18, p 10439 (2022) |
بيانات النشر: | MDPI AG, 2022. |
سنة النشر: | 2022 |
المجموعة: | LCC:Biology (General) LCC:Chemistry |
مصطلحات موضوعية: | HFpEF, diabetes, heart failure, 4-hydroxy-2-nonenal, aldehyde dehydrogenase 2, empagliflozin, Biology (General), QH301-705.5, Chemistry, QD1-999 |
الوصف: | To ameliorate diabetes mellitus-associated heart failure with preserved ejection fraction (HFpEF), we plan to lower diabetes-mediated oxidative stress-induced 4-hydroxy-2-nonenal (4HNE) accumulation by pharmacological agents that either decrease 4HNE generation or increase its detoxification.A cellular reactive carbonyl species (RCS), 4HNE, was significantly increased in diabetic hearts due to a diabetes-induced decrease in 4HNE detoxification by aldehyde dehydrogenase (ALDH) 2, a cardiac mitochondrial enzyme that metabolizes 4HNE. Therefore, hyperglycemia-induced 4HNE is critical for diabetes-mediated cardiotoxicity and we hypothesize that lowering 4HNE ameliorates diabetes-associated HFpEF. We fed a high-fat diet to ALDH2*2 mice, which have intrinsically low ALDH2 activity, to induce type-2 diabetes. After 4 months of diabetes, the mice exhibited features of HFpEF along with increased 4HNE adducts, and we treated them with vehicle, empagliflozin (EMP) (3 mg/kg/d) to reduce 4HNE and Alda-1 (10 mg/kg/d), and ALDH2 activator to enhance ALDH2 activity as well as a combination of EMP + Alda-1 (E + A), via subcutaneous osmotic pumps. After 2 months of treatments, cardiac function was assessed by conscious echocardiography before and after exercise stress. EMP + Alda-1 improved exercise tolerance, diastolic and systolic function, 4HNE detoxification and cardiac liver kinase B1 (LKB1)-AMP-activated protein kinase (AMPK) pathways in ALDH2*2 mice with diabetes-associated HFpEF. This combination was even more effective than EMP alone. Our data indicate that ALDH2 activation along with the treatment of hypoglycemic agents may be a salient strategy to alleviate diabetes-associated HFpEF. |
نوع الوثيقة: | article |
وصف الملف: | electronic resource |
اللغة: | English |
تدمد: | 1422-0067 1661-6596 |
Relation: | https://www.mdpi.com/1422-0067/23/18/10439; https://doaj.org/toc/1661-6596; https://doaj.org/toc/1422-0067 |
DOI: | 10.3390/ijms231810439 |
URL الوصول: | https://doaj.org/article/1643a93fb76d4eecaf0366c5b1d9771b |
رقم الأكسشن: | edsdoj.1643a93fb76d4eecaf0366c5b1d9771b |
قاعدة البيانات: | Directory of Open Access Journals |
تدمد: | 14220067 16616596 |
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DOI: | 10.3390/ijms231810439 |