Dimethylarginine dimethylaminohydrolase (DDAH): expression, regulation, and function in the cardiovascular and renal systems

Abstract

Palm F, Onozato ML, Luo Z, Wilcox CS. Dimethylarginine dimethylaminohydrolase (DDAH): expression, regulation, and function in the cardiovascular and renal systems. Am J Physiol Heart Circ Physiol 293: H3227-H3245, 2007. First published October 12, 2007; doi:10.1152 doi:10. /ajpheart.00998.2007 )-dimethylarginine (ADMA) inhibits nitric oxide (NO) synthases (NOS). ADMA is a risk factor for endothelial dysfunction, cardiovascular mortality, and progression of chronic kidney disease. Two isoforms of dimethylarginine dimethylaminohydrolase (DDAH) metabolize ADMA. DDAH-1 is the predominant isoform in the proximal tubules of the kidney and in the liver. These organs extract ADMA from the circulation. DDAH-2 is the predominant isoform in the vasculature, where it is found in endothelial cells adjacent to the cell membrane and in intracellular vesicles and in vascular smooth muscle cells among the myofibrils and the nuclear envelope. In vivo gene silencing of DDAH-1 in the rat and DDAH ϩ/Ϫ mice both have increased circulating ADMA, whereas gene silencing of DDAH-2 reduces vascular NO generation and endothelium-derived relaxation factor responses. DDAH-2 also is expressed in the kidney in the macula densa and distal nephron. Angiotensin type 1 receptor activation in kidneys reduces the expression of DDAH-1 but increases the expression of DDAH-2. This rapidly evolving evidence of isoform-specific distribution and regulation of DDAH expression in the kidney and blood vessels provides potential mechanisms for nephron site-specific regulation of NO production. In this review, the recent advances in the regulation and function of DDAH enzymes, their roles in the regulation of NO generation, and their possible contribution to endothelial dysfunction in patients with cardiovascular and kidney diseases are discussed. nitric oxide synthase; hypertension; diabetes mellitus; chronic kidney disease; asymmetric dimethylarginineis an endogenous methylated amino acid that inhibits the constitutive endothelial (e) or type III and neuronal (n) or type I isoforms of nitric oxide (NO) synthase (NOS) (49,91,103,199). It is a less potent inhibitor of the inducible (i) or type II NOS isoform (41,191,213). Proteins are subject to methylation of arginine residues by protein arginine methyltransferase (PRMT). S-adenosylmethionine, which is synthesized from methionine and ATP, serves as the methyl donor and, in the process, is converted to S-adenosylhomocysteine, which itself can be hydrolyzed to homocysteine. Remethylation of homocysteine in the "remethylation pathway" regenerates methionine (14,179). ADMA is released by protein hydrolysis and exported from the cell and taken up by other cells via system y ϩ carriers of the cationic amino acid (CAT) family (14,196,212). ADMA is eliminated both by renal excretion and metabolic degradation. Its metabolism is facilitated by dimethylarginine dimethylaminohydrolases (DDAHs), which are expressed as type 1 and 2 isoforms. Recent studies have shown differential sites of expression of DDAH-1 and -2 in blo...

Salt Sensitivity in Blacks

“…[1][2][3] In addition to its capacity to promote the occurrence of hypertension by inhibiting vasodilatation, an ADMA-determined reduction of endothelial NO bioavailability could impair its vasoprotective function and thereby contribute to the pathogenesis of both hypertension and atherosclerosis and consequent cardiovascular morbidity and mortality. 30 The current observations suggest that normotensive salt sensitivity accompanied by NaClinduced increase in plasma ADMA might constitute a pathogenic state worthy of preventive intervention, as with supplemental dietary potassium, 27 particularly in those who are potassium deficient, as blacks often are. 36 …”

“…30,31 O 2 Ϫ scavenges NO, which, by reacting with O 2 Ϫ , is a major endogenous antioxidant. 30,32 Thus, an ADMA-determined decrease in NO formation increases oxidative stress. The increase is self-amplifying in that it can "uncouple" NOS so that it yields not NO but O 2 Ϫ .…”

“…29 Accordingly, the currently observed NaCl-induced selective increase in plasma ADMA could well reflect inhibition of DDAH. DDAH activity is exquisitely sensitive to inhibition by oxidative stress, 29 30,32 Thus, an ADMA-determined decrease in NO formation increases oxidative stress. The increase is self-amplifying in that it can "uncouple" NOS so that it yields not NO but O 2 Ϫ .…”

Asymmetric Dimethylarginine Limits the Efficacy of Simvastatin Activating Endothelial Nitric Oxide Synthase

“…ADMA can be metabolized by DDAH‐1 and DDAH‐2, thereby increasing eNOS‐derived NO bioavailability 19, 20. Thus, DDAH deregulation, which causes ADMA accumulation, is also a risk factor for cardiovascular diseases 19, 20.…”

Role of Dimethylarginine Dimethylaminohydrolases in the Regulation of Endothelial Nitric Oxide Production

“…PCR and Western blot analysis have revealed that the endothelium contains mRNA and protein for both DDAH-1 and DDAH-2 (8,11,14,15,37,41). However, in order to assess the relative contribution of each enzyme, a detailed analysis of the enzyme kinetics of each isoform is necessary.…”