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Transgenic overexpression of GTP cyclohydrolase 1 in cardiomyocytes ameliorates post-infarction cardiac remodeling. Sci Rep 2017 Jun 08;7(1):3093

Date

06/10/2017

Pubmed ID

28596578

Pubmed Central ID

PMC5465102

DOI

10.1038/s41598-017-03234-6

Scopus ID

2-s2.0-85020486126 (requires institutional sign-in at Scopus site)   15 Citations

Abstract

GTP cyclohydrolase 1 (GCH1) and its product tetrahydrobiopterin play crucial roles in cardiovascular health and disease, yet the exact regulation and role of GCH1 in adverse cardiac remodeling after myocardial infarction are still enigmatic. Here we report that cardiac GCH1 is degraded in remodeled hearts after myocardial infarction, concomitant with increases in the thickness of interventricular septum, interstitial fibrosis, and phosphorylated p38 mitogen-activated protein kinase and decreases in left ventricular anterior wall thickness, cardiac contractility, tetrahydrobiopterin, the dimers of nitric oxide synthase, sarcoplasmic reticulum Ca2+ release, and the expression of sarcoplasmic reticulum Ca2+ handling proteins. Intriguingly, transgenic overexpression of GCH1 in cardiomyocytes reduces the thickness of interventricular septum and interstitial fibrosis and increases anterior wall thickness and cardiac contractility after infarction. Moreover, we show that GCH1 overexpression decreases phosphorylated p38 mitogen-activated protein kinase and elevates tetrahydrobiopterin levels, the dimerization and phosphorylation of neuronal nitric oxide synthase, sarcoplasmic reticulum Ca2+ release, and sarcoplasmic reticulum Ca2+ handling proteins in post-infarction remodeled hearts. Our results indicate that the pivotal role of GCH1 overexpression in post-infarction cardiac remodeling is attributable to preservation of neuronal nitric oxide synthase and sarcoplasmic reticulum Ca2+ handling proteins, and identify a new therapeutic target for cardiac remodeling after infarction.

Author List

Liu Y, Baumgardt SL, Fang J, Shi Y, Qiao S, Bosnjak ZJ, Vásquez-Vivar J, Xia Z, Warltier DC, Kersten JR, Ge ZD

Author

Jeannette M. Vasquez-Vivar PhD Professor in the Biophysics department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Calcium
Fibrosis
GTP Cyclohydrolase
Gene Expression
Heart Function Tests
Mice
Myocardial Infarction
Myocytes, Cardiac
Nitric Oxide Synthase Type I
Organ Specificity
Phosphorylation
Sarcoplasmic Reticulum
Transgenes
Ventricular Remodeling