Sepiapterin prevents left ventricular hypertrophy and dilatory remodeling induced by pressure overload in rats

Abstract

Yoshioka K, Otani H, Shimazu T, Fujita M, Iwasaka T, Shiojima I. Sepiapterin prevents left ventricular hypertrophy and dilatory remodeling induced by pressure overload in rats. Am J Physiol Heart Circ Physiol 309: H1782-H1791, 2015. First published September 25, 2015; doi:10.1152/ajpheart.00417.2015.-Uncoupling of nitric oxide (NO) synthase (NOS) has been implicated in left ventricular (LV) hypertrophy (LVH) and dilatory remodeling induced by pressure overload. We investigated whether administration of sepiapterin, a substrate of the salvage pathway of tetrahydrobiopterin synthesis, prevents LVH and dilatory LV remodeling by inhibiting NOS uncoupling and increasing bioavailable NO. Pressure overload was induced in rats by transverse aortic constriction (TAC). Concentric LVH developed during 8 wk after TAC, and dilatory LV remodeling and dysfunction developed between 8 and 16 wk after TAC associated with a decrease in capillary density. Oral administration of sepiapterin or the superoxide/peroxynitrite scavenger N-(2-mercaptopropionyl)-glycine for 8 wk after TAC inhibited oxidative stress, but only sepiapterin increased bioavailable NO and inhibited cardiomyocyte hypertrophy associated with a further increase in capillary density. When sepiapterin was administered between 8 and 16 wk after TAC, cardiomyocyte hypertrophy was regressed and capillary density was restored. This was associated with the inhibition of interstitial fibrosis and dilatory LV remodeling. N-nitro-L-arginine methyl ester abrogated all the beneficial effects of sepiapterin in rats with TAC. These results suggest that sepiapterin prevents concentric LVH and dilatory remodeling after TAC primarily by increasing the bioavailability of NO.

Sepiapterin Improves Vascular Reactivity and Insulin‐Stimulated Glucose in Wistar Rats

“…Animals (male Wistar rats, 8 weeks old), housed 2 animals per cage, were fed a customized diet containing 13% kcal fat (Envigo [Teklad]) for 10 weeks. Animals were randomized into either control ( n = 5) or sepiapterin ( n = 4) groups, and after the first five weeks, the control group continued on the diet and the sepiapterin group was given food containing sepiapterin at 10 mg/kg body weight ad libitum [ 25 , 29 ]. Food consumption was measured and food replaced twice per week.…”

“…Sepiapterin supplementation in diabetic or obese mice resulted in a significant increase in BH 4 , coupled eNOS, and NO production [ 4 , 24 – 27 ], and diabetic mice fed sepiapterin along with L-citrulline showed inhibition of diabetic cardiomyopathy as well as beneficial effects on eNOS dimerization and NO production [ 28 ]. In a rat model of left ventricle hypertrophy, sepiapterin intake attenuated this condition while increasing NO [ 29 ]. These studies demonstrate that sepiapterin restores BH 4 concentrations, eNOS function, and NO production, resulting in downstream functional benefits in the heart; however, the effects of this BH 4 restoration on mitochondrial function and vasoreactivity in sedentary animals are unexamined.…”

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

“…These results are not surprising given that GCH1 is the first and rate-limiting enzyme in the de novo synthesis of BH 4 12 . A growing body of research indicates that BH 4 is a potential therapeutic target for cardiovascular disease, such as hypertension, myocardial ischemia/reperfusion injury, pressure overload-induced cardiac hypertrophy, and diabetic vascular dysfunction 13, 38, 46, 72, 73 . Despite controversy, BH 4 is generally reported to increase eNOS coupling and phosphorylation, elevate NO production, increase tissue cGMP levels, suppress oxidative/nitrosative stress, improve intracellular Ca 2+ homeostasis, elevates SR Ca 2+ cycling, and inhibit inflammation 13, 38, 46, 74, 75 .…”

Morphological and Functional Characteristics of Animal Models of Myocardial Fibrosis Induced by Pressure Overload

“…Its mortality rate and the success rate of the model were 7.14% and 85.71%, respectively [15]. Also myocardial fibrosis can be achieved with 17-gauge needle and 6-0 silk suture at the same observation time [16]. Other studies have shown that cardiac hypertrophy, fibrosis, and dysfunction could also be observed 4 weeks after ligating the rat aortic arch with 27-gauge needle and 7-0 silk suture ligature, presenting as an increase in heart weight index (HW/BW), cross-sectional area of left ventricular myocytes, and interstitial collagen content and a decrease in left ventricular eject fraction [17][18][19].…”