Role of asymmetric dimethylarginine for angiotensin II-induced target organ damage in mice

Abstract

RH, Hilgers KF. Role of asymmetric dimethylarginine for angiotensin II-induced target organ damage in mice. Am J Physiol Heart Circ Physiol 294: H1058-H1066, 2008. First published December 21, 2007 doi:10.1152/ajpheart.01103.2007.-The aim of the present study was to investigate the role of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) and its degrading enzyme dimethylarginine dimethylaminohydrolase (DDAH) in angiotensin II (ANG II)-induced hypertension and target organ damage in mice. Mice transgenic for the human DDAH1 gene (TG) and wild-type (WT) mice (each, n ϭ 28) were treated with 1.0 g ⅐ kg Ϫ1 ⅐ min Ϫ1 ANG II, 3.0 g ⅐ kg Ϫ1 ⅐ min Ϫ1 ANG II, or phosphate-buffered saline over 4 wk via osmotic minipumps. Blood pressure, as measured by tail cuff, was elevated to the same degree in TG and WT mice. Plasma levels of ADMA were lower in TG than WT mice and were not affected after 4 wk by either dose of ANG II in both TG and WT animals. Oxidative stress within the wall of the aorta, measured by fluorescence microscopy using the dye dihydroethidium, was significantly reduced in TG mice. ANG II-induced glomerulosclerosis was similar between WT and TG mice, whereas renal interstitial fibrosis was significantly reduced in TG compared with WT animals. Renal mRNA expression of protein arginine methyltransferase (PRMT)1 and DDAH2 increased during the infusion of ANG II, whereas PRMT3 and endogenous mouse DDAH1 expression remained unaltered. Chronic infusion of ANG II in mice has no effect on the plasma levels of ADMA after 4 wk. However, an overexpression of DDAH1 alleviates ANG II-induced renal interstitial fibrosis and vascular oxidative stress, suggesting a blood pressure-independent effect of ADMA on ANG II-induced target organ damage. dimethylarginine dimethylaminohydrolase; hypertension; transgenic ASYMMETRIC DIMETHYLARGININE (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), is increasingly recognized as a potential risk factor and prognostic biomarker in cardiovascular disease (38). Thus far, elevated ADMA levels have been associated with all established cardiovascular risk factors (38). Furthermore, recent data from genetic mouse models indicate a causal role for ADMA in the pathophysiology of vascular disease (7,19). ADMA derives from the posttranslational methylation of L-arginine residues within proteins catalyzed by enzymes called protein arginine methyltransferases (PRMTs). Upon proteolysis, methylarginines are released into the circulation. Although ϳ15% of ADMA are excreted via the urine, the major elimination occurs through enzymatic degradation (ϳ85%) (1). The enzyme dimethylarginine dimethylaminohydrolase (DDAH), of which two isoforms with distinct tissue distribution have been described, catalyzes the hydrolysis of ADMA to L-citrulline and dimethylamine (38).Thus far, clinical studies have mostly addressed the prognostic value of ADMA in cardiovascular or kidney disease as well as the impact of pharmacological interventions aimed at lowering ADMA levels ...

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.…”

“…DDAH‐1 is predominately expressed in proximal tube kidney and in the liver, whereas DDAH‐2 is the predominant isoform in vascular cells 18, 19. Recent research found that overexpression of DDAH‐1 reduced ADMA levels and angiotensin II–induced hypertension in mice 20. Additionally, overexpression of DDAH‐1 ameliorated atherosclerosis by lowering ADMA level in apolipoprotein E–deficient (apoE −/− ) mice 21.…”

Reduced Renal Methylarginine Metabolism Protects against Progressive Kidney Damage

“…ADMA or L-NAME infusion into mice exacerbated renal fibrosis, but both raised SBP by approximately 60 mmHg, suggesting hypertensive injury 28 ; global DDAH1 overexpression, however, protected against fibrosis in angiotensin and surgical nephron-reduction models of CKD. 29,30 Genetic DDAH1 overexpression decreases circulating ADMA and introduces unmeasured effects upon normal regulatory mechanisms. Furthermore, DDAH1 overexpression occurs indiscriminately in cell types that do not normally express DDAH1, but play significant roles in inflammation and fibrosis (e.g., macrophages).…”

Asymmetric dimethylarginine in angiotensin II-induced hypertension

“…There are also conflicting reports on the effects of administration of exogenous ANG II on ADMA in vivo. Whereas Hasegawa and colleagues (14) showed that 2 wk of ANG II infusion in mice resulted in a 100% increase in plasma ADMA, Jacobi et al (19) found no effect of 4 wk of ANG II infusion on plasma ADMA levels. These studies did not examine the effects of ANG II infusion on tissue levels of ADMA.…”