The VV genotype of MTHFR was also common in the Japanese population and was significantly associated with CAD. The frequency of this genotype in particular was correlated with the severity of disease. The VV genotype associated with a predisposition to increased plasma homocyst(e)ine levels may represent a genetic risk factor for CAD.

Abstract-In this study, we investigated the regulation and physiological role of heme oxygenase-1 (HO-1) in the kidney of rats with hypertension. Rats were continuously administered either angiotensin II (Ang II) or norepinephrine with an osmotic minipump for up to 7 days. Ang II infusion decreased the glomerular filtration rate (GFR) as determined through creatinine clearance (3.2Ϯ0. Key Words: hypertension Ⅲ angiotensin II Ⅲ proteinuria Ⅲ oxidative stress Ⅲ kidney H ypertension induces structural and functional alterations in the kidney, eventually leading to end-stage renal disease. The control of blood pressure retards the progression of renal failure and reduces the morbidity and mortality rates associated with hypertensive vascular disease. 1,2 Although several clinical trials have shown a similar slowing of the progression with the use of either ACE inhibitors or other antihypertensive drugs, 3 the superiority of ACE inhibitors has been demonstrated in some studies. Compared with other classes of antihypertensive drugs, ACE inhibitors were more effective than other agents in preservation of the glomerular filtration rate 4 and in their antiproteinuric effects 5,6 in essential hypertension. The extra effectiveness of ACE inhibitors may derive from their ability to preferentially dilate the efferent arterioles 7 and their antiproliferative effects. 8 Heme oxygenase (HO) is a rate-limiting enzyme of heme catabolism that has 2 isoforms: HO-1, an inducible form, 9,10 and HO-2, a constitutive form. Induced HO-1 is thought to act as an antioxidative and anti-inflammatory defense mechanism through the degradation of cellular heme (pro-oxidant) and increase in biliverdin (antioxidant 11 ). The carbon monoxide (CO) that is produced also has physiological functions, such as vascular relaxation 12 and inhibition of platelet aggregation, 13 through the activation of soluble guanylyl cyclase. The recent findings that HO-1 gene transfer ameliorated oxidative tissue injury 14 and that oxidant-induced cellular injury was increased in HO-1 knockout mice 15 and in human HO-1 deficiency 16 provide further direct evidence that HO-1 acts favorably against oxidative stress. In the kidney, both HO-1 and HO-2 are present in the tubular epithelial cells, 17,18 suggesting that the HO system also plays a role in the kidney. In fact, HO-1 induction exerts a protective effect on renal function in animal models of rhabdomyolysis, 19 cisplatin nephrotoxicity, 20 and nephrotoxic nephritis. 21 In previous reports, we demonstrated that HO-1 expression was regulated by Ang II in vascular smooth muscle in both pressordependent 22 and pressor-independent 23 manners.Renal damage occurs via pressor-dependent and -independent mechanisms. The present study was designed to examine both such mechanisms in the angiotensin II (Ang II)

Abstract-Nitric oxide (NO) derived from endothelial cells is profoundly related to the maintenance of physiological vascular tone. Impairment of endothelial NO generation brought about by gene polymorphism is considered the major deterioration factor for progressive renal disease, including diabetic nephropathy. The present study aimed to elucidate the Glu298Asp polymorphism of endothelial NO synthase (eNOS) in patients with end-stage renal disease (ESRD) and its role as a predisposing factor for cardiovascular complications. Glu298Asp in exon 7 of the eNOS gene was determined by polymerase chain reaction, followed by restriction fragment length polymorphism analysis, in ESRD patients (nϭ185) and compared with that of unrelated healthy individuals (nϭ304). Key Words: polymorphism Ⅲ polymerase chain reaction Ⅲ nitric oxide synthase Ⅲ diabetes mellitus T he endothelial isoform of nitric oxide (NO) synthase (eNOS, NOSIII) is a constitutively expressed 135 kDa protein predominantly associated with the particulated specific structures in the plasmalemmal membrane, caveolae, of vascular endothelial cells. 1,2 NO is produced from L-arginine and diffuses to vascular smooth muscle cells, where it increases the concentration of cGMP by stimulating soluble guanylate cyclase, leading to vascular relaxation. It also inhibits platelet and/or leukocyte adhesion to vascular endothelium. Therefore, the impairment of eNOS expression has been considered a primary factor for diseases such as hypertension, coronary artery disease, thromboembolic diseases, and atherosclerosis. Indeed, knocking out the gene encoding eNOS in mice resulted in significant hypertension, and aortic rings from these animals studied ex vivo displayed no relaxation in response to acetylcholine. 3 Patients with endstage renal disease (ESRD) derived from diabetes mellitus (DM) nephropathy have a higher prevalence of cardiovascular complications than those with non-DM ESRD, and this limits their 5-year survival rate to less than 50%. Therefore, polymorphism in eNOS is considered one of the major predisposing factors for endothelial dysfunction.The gene polymorphisms of eNOS have been detected at 4b/4a variable number of tandem repeats in intron 4, Glu298Asp in exon 7, CA repeat in intron 13, A27 to C (A to C nucleotide conversion) in intron 18, and G10 to T in intron 23. A part of candidate variations (4b/4a tandem repeats in intron 4) has been investigated in glomerulonephritis and/or ESRD patients, but no conclusive results have been obtained so far. Recently, the G/T polymorphism in exon 7 coding for Glu298Asp was detected and reported to have a remarkable association with coronary spasm, acute myocardial infarction, 4 and hypertension. 5 To date, this is the only known eNOS polymorphism associated with an altered protein sequence, though recent expression studies have demonstrated no functional difference between 298Glu and 298Asp despite the accumulating clinical evidence. 6,7

Objective-Heme oxygenase (HO) is important in the defense against oxidative stress and as a factor in an antiatherogenic mechanism. Compared with long (GT) n repeats, short (GT) n repeats in the human HO-1 gene promoter were shown to have higher transcriptional activity in response to oxidative stress. There is a strong link between oxidative stress and the pathogenesis of coronary artery disease (CAD). Methods and Results-We screened the allelic frequencies of (GT) n repeats in the HO-1 gene promoter in 577 patients who underwent coronary angiography. Because the distribution of numbers of (GT) n repeats was bimodal, we divided the alleles into 2 subclasses: class S included shorter (Ͻ27) repeats, and class L included longer (Ն27) repeats. Multivariate logistic regression models including standard coronary risk factors revealed that the genotypes were significantly related to CAD status in hypercholesterolemic, diabetic patients or in smokers. In this study, the patients with shorter GT repeats were less likely to have CAD. Conclusions-Length

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Neurosin, a novel type of trypsin-like serine protease, has been shown to be preferentially expressed in human brain by northern blotting. We examined neurosin immunolabeling in the brains of neurologically normal persons and patients with Alzheimer's disease (AD) and with Parkinson's disease. We also identified the expression of the mRNA for neurosin by in situ hybridization histochemistry and reverse transcription-polymerase chain reaction (RT-PCR).The neurosin antibody stained all of the nuclei of various cell types. In neurons, there was also staining of neuronal cytoplasm, nucleoli and their processes. In AD, staining of neurons with processes was rare in the damaged areas. Some senile plaques, extracellular tangles and Lewy bodies were also positive for neurosin. Expression of the mRNA for neurosin was seen in neurons in the gray matter, and in microglial cells in the white matter. In AD, the intensity of the signal for neurosin mRNA in the gray matter was decreased compared with normal control brains. The relative levels of neurosin mRNA in AD brains, measured by RT-PCR, were lower than those in controls. These results suggest that in human brain neurosin plays various physiological roles, and that in AD this molecule, like other serine proteases, may have a role in the degradation of such substances as b-amyloid protein.

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