Transgenic overexpression of GTP cyclohydrolase 1 in cardiomyocytes ameliorates post-infarction cardiac remodeling

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.

Failure of Isoflurane Cardiac Preconditioning in Obese Type 2 Diabetic Mice Involves Aberrant Regulation of MicroRNA-21, Endothelial Nitric-oxide Synthase, and Mitochondrial Complex I

“…The heart was excised, and the left ventricle was homogenized at 4 °C for real-time quantitative reverse transcriptional-polymerase chain reaction analysis of microRNA-21. 26…”

“…27 Briefly, non-boiled protein lysate that contained 50 μg of protein was resolved by 6% sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) at 4 °C overnight. 26 Membranes were incubated with a 1:2000 dilution of mouse anti-eNOS monoclonal antibodies (BD Transduction Laboratories, San Jose, CA). The membrane was washed and then incubated with the appropriate anti-mouse secondary antibody.…”

Empagliflozin improves post-infarction cardiac remodeling through GTP enzyme cyclohydrolase 1 and irrespective of diabetes status

“…Several studies have showed as cGCH1, which is the rate-limiting enzyme in de novo synthesis of BH4, is down-regulated during adverse cardiac remodeling affecting to cardiac function 6 , 24 , 25 . In 2016 Wu et al, established that cGCH1 could be a potential therapeutic target for treatment of MI in the clinic 6 , as revealed by another study published later in showing that transgenic overexpression of cGCH1 in cardiomyocytes ameliorates cardiac remodeling following MI 26 . These authors also revealed that an transgenic overexpression of cGCH1 protein is related to a lower infarcted size 26 .…”

“…In 2016 Wu et al, established that cGCH1 could be a potential therapeutic target for treatment of MI in the clinic 6 , as revealed by another study published later in showing that transgenic overexpression of cGCH1 in cardiomyocytes ameliorates cardiac remodeling following MI 26 . These authors also revealed that an transgenic overexpression of cGCH1 protein is related to a lower infarcted size 26 . In the current study, we show that cGCH1 expression is decreased in failing hearts and cardiomyocytes under stretching (Fig.…”

Interplay of the red blood cell and vascular endothelial nitric oxide synthase system to combat cardiac complications of anemia

“…Also exogenous administration of tetrahydrobiopterin (BH 4 ), an essential cofactor for eNOS function, improved ischemic damage in isolated hearts subjected to I/R [27,29]. Likewise, cardiac-specific overexpression of GTP-cyclohydrolase-1, the rate-limiting enzyme for tetrahydrobiopterin synthesis, improved ischemic preconditioning [12] and also attenuated post-infarction cardiac remodeling [16], most probably by restoration of tetrahydrobiopterin synthesis and thus by the prevention of eNOS uncoupling [10]. Further support of this concept is provided by genetic models, where eNOS knockout mice showed more pronounced ischemic damage, myocardial fibrosis and impaired left-ventricular end-diastolic volume and ejection fraction, when subjected to myocardial infarction [25].…”