Decreased cardiac mitochondrial tetrahydrobiopterin in a rat model of pressure overload

Abstract

Abstract. Sustained cardiac pressure overload induces mitochondrial dysfunction and apoptosis of cardiomyocytes leading to pathological cardiac hypertrophy and dysfunction. Mitochondrial nitric oxide synthase (NOS) appears to cause uncoupling, which produces reactive oxygen species (ROS) instead of nitric oxide (NO), by a decrease in the cofactor tetrahydrobiopterin (BH4). This study focused on examining the changes in mitochondrial BH4 levels during cardiac pressure overload. Chronic cardiac pressure overload was generated by abdominal aortic banding in rats. Levels of BH4 and its oxidized form were measured in the mitochondria isolated from the left ventricle (LV) and the post-mitochondrial supernatants. Chronic aortic banding increased blood pressure, and induced cardiac hypertrophy and fibrosis. Notably, the BH4 levels were decreased while its oxidized forms were increased in LV mitochondria, but not in the post-mitochondrial supernatants containing the cytosol and microsome. Anti-neuronal NOS antibody-sensitive protein was detected in the cardiac mitochondria. Moreover, continuous administration of BH4 to rats with pressure overload increased mitochondrial BH4 levels and reduced cardiac fibrosis and matrix metallopeptidase activity, but not cardiac hypertrophy. These findings show the possibility that NOS uncoupling by decreased cardiac mitochondrial BH4 levels is implicated, at least in part, in the development of cardiac fibrosis, leading to cardiac dysfunction induced by pressure overload.

A novel role for endothelial tetrahydrobiopterin in mitochondrial redox balance

“…BH 4 is a redox-active molecule and oxidation to BH 2 plays a significant part in the decreased bioavailability observed in disease states. In accordance with previous reports [22], [23], [24], we have detected biopterins in mitochondria. We also evidence lower levels of BH 4 in the mitochondria of BH 4 -depleted cells and show that, of the remaining, a greater proportion is oxidised.…”

“…Whilst both mitochondrial biopterins and GTPCH localisation have previously been reported [22], [23], [24], the concept of GTPCH producing BH 4 specifically within the mitochondrial compartment is one that merits more thorough investigation. Similarly, BH 4 transport is poorly understood, although it has been suggested that cellular uptake of BH 4 possibly occurs via either urate transporters (URAT1), organic anion transporters (OATs), or multidrug-resistance-associated proteins (MRPs) in the kidney [25].…”

BH4 activates CaMKK2 and rescues the cardiomyopathic phenotype in rodent models of diabetes

“…In previous studies, BH4 has been reported to be compartmentalized in the cytoplasm and mitochondria. Interestingly, the concentration of BH4 was more than three times higher in mitochondria than in cardiac tissue (Shimizu et al, 2013), suggesting different roles for BH4 in each compartment. In 1972, Rembold and Buff discovered the direct effect of BH4 on the mitochondrial electron transfer chain using isolated mitochondria and sub-mitochondrial particles (Rembold & Buff, 1972).…”

Tetrahydrobiopterin (BH4): Targeting endothelial nitric oxide synthase as a potential therapy for pulmonary hypertension

“…Plenty of experiments showed that NOS is a key determinant of left ventricular function . Whether NOS plays a similar function in the right ventricle remains to be determined.…”

“…Cardiac function is influenced by eNOS activity . Pressure overload reduces cardiac BH 4 in conjunction with eNOS uncoupling leading to dilatory remodeling, left ventricular hypertrophy, and fibrosis . BH 4 treatment ameliorated preexisting left ventricular hypertrophy and fibrosis .…”