Roles of accumulated endogenous nitric oxide synthase inhibitors, enhanced arginase activity, and attenuated nitric oxide synthase activity in endothelial cells for pulmonary hypertension in rats

Abstract

Sasaki A, Doi S, Mizutani S, Azuma H. Roles of accumulated endogenous nitric oxide synthase inhibitors, enhanced arginase activity, and attenuated nitric oxide synthase activity in endothelial cells for pulmonary hypertension in rats. Am J Physiol Lung Cell Mol Physiol 292: L1480-L1487, 2007. First published February 23, 2007 doi:10.1152/ajplung.00360.2006 has been suggested to play a key role in the pathogenesis of pulmonary hypertension (PH). To determine which mechanism exists to affect NO production, we examined the concentration of endogenous nitric oxide synthase (NOS) inhibitors and their catabolizing enzyme dimethylarginine dimethylaminohydrolase (DDAH) activity and protein expression (DDAH1 and DDAH2) in pulmonary artery endothelial cells (PAECs) of rats given monocrotaline (MCT). We also measured NOS and arginase activities and NOS protein expression. Twenty-four days after MCT administration, PH and right ventricle (RV) hypertrophy were established. Endothelium-dependent, but not endothelium-independent, relaxation and cGMP production were significantly impaired in pulmonary artery specimens of MCT group. The constitutive NOS activity and protein expression in PAECs were significantly reduced in MCT group, whereas the arginase, which shares L-arginine as a common substrate with NOS, activity was significantly enhanced in PAECs of MCT group. The contents of monomethylarginine (MMA) and asymmetric dimethylarginine (ADMA), but not symmetric dimethylarginine (SDMA), were increased in PAECs of MCT group. The DDAH activity and DDAH1, but not DDAH2, protein expression were significantly reduced in PAECs of MCT group. These results suggest that the impairment of cGMP production as a marker of NO production is possibly due to the blunted endothelial NOS activity resulting from the downregulation of endothelial NOS protein, accumulation of endogenous NOS inhibitors, and accelerated arginase activity in PAECs of PH rats. The decreased overall DDAH activity accompanied by the downregulation of DDAH1 would bring about the accumulation of endogenous NOS inhibitors.L-arginine-nitric oxide pathway; dimethylarginine dimethylaminohydrolase PULMONARY HYPERTENSION (PH) is a fatal disease characterized by intimal and medial hyperplasia and adventitial fibrosis in peripheral pulmonary arteries. Impairment of endogenous release of nitric oxide (NO), which causes vasodilation (38) and inhibition of both platelet aggregation (3) and vascular smooth muscle cell proliferation (17), has been proposed to be important in developing the PH (1, 13). Actually, under clinical settings, NO level in lung tissue is lower in patients with PH compared with healthy controls (22), and NO inhalation is a specific pulmonary vasodilator therapy (39). In addition, it has been reported that short-term oral administration of L-arginine improves hemodynamics and exercise capacity in patients with precapillary PH (35).NO production, on one hand, depends on the nitric oxide synthase (NOS) activity and protein expression. There is a report describin...

Arginase inhibition prevents bleomycin-induced pulmonary hypertension, vascular remodeling, and collagen deposition in neonatal rat lungs

“…There are three distinct isoforms: NOS1, NOS2, and NOS3. Arginase competes with NOS for L-arginine under physiological conditions (61), and induction of arginase activity in the pulmonary circulation leads to a decrease in endothelial NO synthesis from NOS3 (48,63), a fundamental feature of many cardiovascular disorders. The proliferative and fibrotic effects of arginase activity may be further amplified by the competition of arginase I and NOS2 for L-arginine as substrate that restricts the generation of NO, which is an established inhibitor of SMC proliferation and collagen synthesis (17,30).…”

Possible Involvement of Altered Arginase Activity, Arginase Type I and Type II Expressions, and Nitric Oxide Production in Occurrence of Intimal Hyperplasia in Premenopausal Human Uterine Arteries

“…It has been reported that the enhanced arginase activity decreases L-arginine availability to NOS, thus impairing NO production (17). Enhanced arginase activity has been implicated in a number of conditions characterized by vascular dysfunction including pulmonary hypertension (18), intimal hyperplasia (19), agingassociated vascular dysfunction (20,21), and smokingrelated vascular dysfunction (22).…”

Is arginase a potential drug target in tobacco-induced pulmonary endothelial dysfunction?

“…primary or secondary PH [22,[28][29][30][31][32]. To the best of our knowledge, our study is the first to have demonstrated the role of increased arginase activity in tobacco associatedpulmonary endothelial dysfunction.…”