Intermedin Alleviates Diabetic Cardiomyopathy by Up-Regulating CPT-1β through Activation of the Phosphatidyl Inositol 3 Kinase/Protein Kinase B Signaling Pathway.

Autor: Zhao J; Laboratory of Cardiovascular Bioactive Molecule, School of Basic Medical Sciences, Peking University, Beijing 100083, China.; State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100083, China.; Department of Pathogen Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100083, China., Han L; Department of Cardiology, Fuxing Hospital, Capital Medical University, Beijing 100038, China., Zhang YR; Laboratory of Cardiovascular Bioactive Molecule, School of Basic Medical Sciences, Peking University, Beijing 100083, China.; State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100083, China.; Department of Pathogen Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100083, China., Liu SM; Laboratory of Cardiovascular Bioactive Molecule, School of Basic Medical Sciences, Peking University, Beijing 100083, China.; State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100083, China.; Department of Pathogen Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100083, China., Ji DR; Laboratory of Cardiovascular Bioactive Molecule, School of Basic Medical Sciences, Peking University, Beijing 100083, China.; State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100083, China.; Department of Pathogen Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100083, China., Wang R; Laboratory of Cardiovascular Bioactive Molecule, School of Basic Medical Sciences, Peking University, Beijing 100083, China.; State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100083, China.; Department of Pathogen Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100083, China., Yu YR; Laboratory of Cardiovascular Bioactive Molecule, School of Basic Medical Sciences, Peking University, Beijing 100083, China.; State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100083, China.; Department of Pathogen Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100083, China., Jia MZ; Laboratory of Cardiovascular Bioactive Molecule, School of Basic Medical Sciences, Peking University, Beijing 100083, China.; State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100083, China.; Department of Pathogen Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100083, China., Chai SB; Department of Endocrinology and Metabolism, Peking University International Hospital, Beijing 102206, China., Tang HF; Department of Cardiology Laboratory, First Affiliated Hospital of University of South China, Hengyang 421001, China., Huang W; State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100083, China.; Institute of Cardiovascular Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100083, China., Qi YF; Laboratory of Cardiovascular Bioactive Molecule, School of Basic Medical Sciences, Peking University, Beijing 100083, China.; State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100083, China.; Department of Pathogen Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100083, China.
Jazyk: angličtina
Zdroj: Pharmaceuticals (Basel, Switzerland) [Pharmaceuticals (Basel)] 2024 Sep 12; Vol. 17 (9). Date of Electronic Publication: 2024 Sep 12.
DOI: 10.3390/ph17091204
Abstrakt: Diabetic cardiomyopathy (DCM), one of the most serious long-term consequences of diabetes, is closely associated with myocardial fatty acid metabolism. Carnitine palmitoyltransferase-1β (CPT-1β) is the rate-limiting enzyme responsible for β-oxidation of long-chain fatty acids. Intermedin (IMD) is a pivotal bioactive small molecule peptide, participating in the protection of various cardiovascular diseases. However, the role and underlying mechanisms of IMD in DCM are still unclear. In this study, we investigated whether IMD alleviates DCM via regulating CPT-1β. A rat DCM model was established by having rats to drink fructose water for 12 weeks. A mouse DCM model was induced by feeding mice a high-fat diet for 16 weeks. We showed that IMD and its receptor complexes levels were significantly down-regulated in the cardiac tissues of DCM rats and mice. Reduced expression of IMD was also observed in neonatal rat cardiomyocytes treated with palmitic acid (PA, 300 μM) in vitro. Exogenous and endogenous IMD mitigated cardiac hypertrophy, fibrosis, dysfunction, and lipid accumulation in DCM rats and IMD-transgenic DCM mice, whereas knockout of IMD worsened these pathological processes in IMD-knockout DCM mice. In vitro, IMD alleviated PA-induced cardiomyocyte hypertrophy and cardiac fibroblast activation. We found that CPT-1β enzyme activity, mRNA and protein levels, and acetyl-CoA content were increased in T2DM patients, rats and mice. IMD up-regulated the CPT-1β levels and acetyl-CoA content in T2DM rats and mice. Knockdown of CPT-1β blocked the effects of IMD on increasing acetyl-CoA content and on inhibiting cardiomyocyte hypertrophy and cardiac fibroblast activation. IMD receptor antagonist IMD 17-47 and the phosphatidyl inositol 3 kinase (PI3K)/protein kinase B (Akt) inhibitor LY294002 reversed the effects of IMD on up-regulating CPT-1β and acetyl-CoA expression and on inhibiting cardiomyocyte hypertrophy and cardiac fibroblast activation. We revealed that IMD alleviates DCM by up-regulating CPT-1β via calcitonin receptor-like receptor/receptor activity-modifying protein (CRLR/RAMP) receptor complexes and PI3K/Akt signaling. IMD may serve as a potent therapeutic target for the treatment of DCM.
Databáze: MEDLINE
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