We speculate that the positive-feedback loop (Erk1/2-NF-kB-MCP-1-Erk1/2) is associated with progression of PAH by causing FGF₂-induced inflammation in MCT rats. IMD-0354 has potential as a new therapeutic tool for PAH.

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...

Cigarette smoking is an independent risk factor for vasculogenic erectile dysfunction (ED). Nitric oxide (NO) has been demonstrated to be the principal mediator of cavernous smooth muscle relaxation and penile erection. Therefore, we examined whether or not enzyme activities and factors involved in the NO generation pathway are affected in rabbit corpus cavernosum after administration of nicotine-and tar-free cigarette smoke extract (CSE). CSE was prepared by bubbling a stream of cigarette smoke into phosphate-buffered saline. CSE was injected subcutaneously into adult male rabbits once a day for 5 wk. In the CSE group, significantly decreased cyclic GMP production as a marker of NO generation was associated with attenuated overall nitric oxide synthase (NOS) activity, enhanced arginase activity, accumulation of endogenous NOS inhibitors such as monomethylarginine (MMA) and asymmetric dimethylarginine (ADMA), and decreased dimethylarginine dimethylaminohydrolase (DDAH) activity as an metabolizing enzyme of endogenous NOS inhibitors. Neuronal NOS (nNOS) and DDAH I protein expression were decreased without altering endothelial NOS expression, while arginase I expression was upregulated. These results suggest that impaired NO production would result from blunted NOS activity, which is possibly brought about by the downregulation of nNOS protein, accumulation of endogenous NOS inhibitors, and enhanced arginase activity together with upregulation of arginase I protein in cavernous tissue. The impaired DDAH activity due to decreased expression of DDAH I protein would result in an accumulation of endogenous NOS inhibitors with CSE. These alterations may be relevant to induction of the erectile dysfunction following CSE. erectile dysfunction; nitric oxide generation pathway; anti-asymmetric dimethylarginine antibody; immunohistochemistry; Western blot ACCORDING TO FELDMAN ET AL. (18) and McVary et al. (39), there are strong parallels and shared risks among smoking, coronary artery disease, atherosclerosis, and erectile dysfunction (ED). Clinical and basic science studies provide strong indirect evidence that smoking may affect penile erection by impairment of endothelium-dependent smooth muscle relaxation. Numerous studies have shown endothelial dysfunction in ED in smokers and experimental models. A recent review summarized some proposed mechanisms such as the way in which free radicals and aromatic compounds decrease the endothelial synthesis of nitric oxide (NO), causing impaired endotheliumdependent relaxation of arteries, which is the earliest clinical sign of endothelial dysfunction (45). NO has been demonstrated to be the principal mediator of cavernous smooth muscle relaxation and penile erection (4, 14, 24, 30, 46 -48). However, the precise mechanisms of impairment of NO production with cigarette smoking have not been fully elucidated.NO production, on one hand, depends on nitric oxide synthase (NOS) activity and NOS protein expression. There are reports describing that NOS activity was decreased in the human ...

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Receptor-like kinases (RLKs) constitute a large family of signal perception molecules. We characterized two highly homologous RLK genes, RLK902 and RKL1, in Arabidopsis. RLK902 and RKL1 showed a 75% amino acid sequence identity over their entire regions. In the RLK902 pro::GUS transgenic lines, GUS activity was strong in the root tips, lateral root primordia, stipules, and floral organ abscission zones, while the RKL1 promoter activity was dominant in the stomata cells, hydathodes and trichomes of young rosette leaves, and floral organ abscission zones. Neither the rlk902 mutant line, rkl1 mutant line nor rlk902/rkl1 double-knockout mutant line showed any significant phenotypes under normal growth conditions. These results suggest that RLK902 and RKL1 might mediate the signal transduction pathway in which at least one other complementary signaling pathway to these two RLKs might exist.