Vinpocetine Attenuates Pathological Cardiac Remodeling by Inhibiting Cardiac Hypertrophy and Fibrosis.
OBJECTIVE
Pathological cardiac remodeling, characterized by cardiac hypertrophy and fibrosis, is a pathological feature of many cardiac disorders that leads to heart failure and cardiac arrest. Vinpocetine, a derivative of the alkaloid vincamine, has been used for enhancing cerebral blood flow to treat cognitive impairment. However, its role in pathological cardiac remodeling remains unknown. The aim of this study is to examine the effect of vinpocetine on pathological cardiac remodeling induced by chronic stimulation with angiotensin II (Ang II).


METHODS
Mice received Ang II infusion via osmotic pumps in the presence of vehicle or vinpocetine. Cardiac hypertrophy and fibrosis were assessed by morphological, histological, and biochemical analyses. Mechanistic studies were carried out in vitro with isolated mouse adult cardiac myocytes and fibroblasts.


RESULTS
We showed that chronic Ang II infusion caused cardiac hypertrophy and fibrosis, which were all significantly attenuated by systemic administration of vinpocetine. In isolated adult mouse cardiomyocytes, vinpocetine suppressed Ang II-stimulated myocyte hypertrophic growth. In cultured cardiac fibroblasts, vinpocetine suppressed TGFβ-induced fibroblast activation and matrix gene expression, consistent with its effect in attenuating cardiac fibrosis. The effects of vinpocetine on cardiac myocyte hypertrophy and fibroblast activation are likely mediated by targeting cyclic nucleotide phosphodiesterase 1 (PDE1).


CONCLUSIONS
Our results reveal a novel protective effect of vinpocetine in attenuating pathological cardiac remodeling through suppressing cardiac myocyte hypertrophic growth and fibroblast activation and fibrotic gene expression. These studies may also shed light on developing novel therapeutic agents for antagonizing pathological cardiac remodeling.
Department of Cardiology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200071, China.|Aab Cardiovascular Research Institute, School of Medicine and Dentistry, University of Rochester, 601 Elmwood Ave, Box CVRI, Rochester, NY, 14642, USA.
Mei-Ping
MP
Wu
Aab Cardiovascular Research Institute, School of Medicine and Dentistry, University of Rochester, 601 Elmwood Ave, Box CVRI, Rochester, NY, 14642, USA.
Yi-Shuai
YS
Zhang
Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, NY, 14642, USA.
Xiangbin
X
Xu
Aab Cardiovascular Research Institute, School of Medicine and Dentistry, University of Rochester, 601 Elmwood Ave, Box CVRI, Rochester, NY, 14642, USA.
Qian
Q
Zhou
Center for Inflammation, Immunity & Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, 30302, USA. jdli@gsu.edu.
Jian-Dong
JD
Li
Department of Cardiology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200071, China. chen_yan@urmc.rochester.edu.|Aab Cardiovascular Research Institute, School of Medicine and Dentistry, University of Rochester, 601 Elmwood Ave, Box CVRI, Rochester, NY, 14642, USA. chen_yan@urmc.rochester.edu.
Chen
http://orcid.org/0000-0002-1397-6358
C
Yan
D000804:Angiotensin II; D000818:Animals; D006332:Cardiomegaly / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D009202:Cardiomyopathies / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019610:Cytoprotection; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D008297:Male; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects*; D014748:Vinca Alkaloids / Q000494:pharmacology*
D016326:Extracellular Matrix Proteins; D010726:Phosphodiesterase Inhibitors; D014748:Vinca Alkaloids; D000804:Angiotensin II; C013983:vinpocetine; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1
Cardiac fibrosis; Cardiac hypertrophy; Cardiac remodeling; PDE1; Vinpocetine