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Intermedin alleviates pathological cardiac remodeling by upregulating klotho.
Zhang, Lin-Shuang; Liu, Yan; Chen, Yao; Ren, Jin-Ling; Zhang, Ya-Rong; Yu, Yan-Rong; Jia, Mo-Zhi; Ning, Zhong-Ping; Du, Jie; Tang, Chao-Shu; Qi, Yong-Fen.
Affiliation
  • Zhang LS; Laboratory of Cardiovascular Bioactive Molecule, School of Basic Medical Sciences, Peking University, Beijing, 100083, China; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University Health Science Center, Beijing, 100083, China; Department of Pathogen Biology, Sc
  • Liu Y; Key Laboratory of Remodeling-Related Cardiovascular Diseases, Beijing Institute of Heart, Lung, and Blood Vessel Diseases, Beijing An Zhen Hospital, Ministry of Education, Capital Medical University, Beijing, 100029, China.
  • Chen Y; Laboratory of Cardiovascular Bioactive Molecule, School of Basic Medical Sciences, Peking University, Beijing, 100083, China; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University Health Science Center, Beijing, 100083, China; Department of Pathogen Biology, Sc
  • Ren JL; Laboratory of Cardiovascular Bioactive Molecule, School of Basic Medical Sciences, Peking University, Beijing, 100083, China; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University Health Science Center, Beijing, 100083, China; Department of Pathogen Biology, Sc
  • Zhang YR; Laboratory of Cardiovascular Bioactive Molecule, School of Basic Medical Sciences, Peking University, Beijing, 100083, China; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University Health Science Center, Beijing, 100083, China; Department of Pathogen Biology, Sc
  • Yu YR; Department of Pathogen Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100083, China.
  • Jia MZ; Department of Pathogen Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100083, China.
  • Ning ZP; Shanghai University of Medicine and Health Sciences, Shanghai University of Medicine and Health Sciences Affiliated Zhoupu Hospital, Shanghai, China.
  • Du J; Key Laboratory of Remodeling-Related Cardiovascular Diseases, Beijing Institute of Heart, Lung, and Blood Vessel Diseases, Beijing An Zhen Hospital, Ministry of Education, Capital Medical University, Beijing, 100029, China.
  • Tang CS; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, 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; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University Health Science Center, Beijing, 100083, China; Department of Pathogen Biology, Sc
Pharmacol Res ; 159: 104926, 2020 09.
Article in En | MEDLINE | ID: mdl-32502636
Cardiac remodeling is accompanied by cardiac hypertrophy, fibrosis, dysfunction, and eventually leading to heart failure. Intermedin (IMD), as a paracrine/autocrine peptide, has a protective effect in cardiovascular diseases. In this study, we elucidated the role and the underlying mechanism of IMD in pathological remodeling. Pathological remodeling mouse models were induced by abdominal aorta constriction for 4 weeks or angiotensin II (Ang II) infusion for 2 weeks in wildtype, IMD-overexpression, IMD-knockout and klotho-knockdown mice. Western blot, real-time PCR, histological staining, echocardiography and hemodynamics were used to detect the role of IMD in cardiac remodeling. Cardiac hypertrophy, fibrosis and dysfunction were significantly aggravated in IMD-knockout mice versus wildtype mice, and the expression of klotho was downregulated. Conversely, cardiac remodeling was alleviated in IMD-overexpression mice, and the expression of klotho was upregulated. Hypertension induced by Ang II infusion rather than abdominal aorta constriction was mitigated by IMD. However, the cardioprotective effect of IMD was blocked in klotho-knockdown mice. Similar results were found in cultured neonatal rat cardiomyocytes, which was pretreated with IMD before Ang II stimulation. Mechanistically, IMD inhibited the phosphorylation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) and the activity of calcineurin to protect against cardiac hypertrophy through upregulating klotho in vivo and in vitro. Furthermore, peroxisome proliferator-activated receptor γ (PPARγ) might mediate IMD upregulating klotho. In conclusion, pathological remodeling may be alleviated by endogenous IMD, which inhibits the expression of calcineurin and p-CaMKII by upregulating klotho via the PPARγ pathway. It suggested that IMD might be a therapeutic target for heart disease.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Neuropeptides / Ventricular Function, Left / Hypertrophy, Left Ventricular / Ventricular Dysfunction, Left / Ventricular Remodeling / Myocytes, Cardiac / Glucuronidase Limits: Animals Language: En Journal: Pharmacol Res Journal subject: FARMACOLOGIA Year: 2020 Document type: Article Country of publication: Netherlands

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Neuropeptides / Ventricular Function, Left / Hypertrophy, Left Ventricular / Ventricular Dysfunction, Left / Ventricular Remodeling / Myocytes, Cardiac / Glucuronidase Limits: Animals Language: En Journal: Pharmacol Res Journal subject: FARMACOLOGIA Year: 2020 Document type: Article Country of publication: Netherlands