Epigallocatechin-3-gallate ameliorates erectile function in aged rats via regulation of PRMT1/DDAH/ADMA/NOS metabolism pathway

Abstract

Aging-related ED is predominantly attributed to neurovascular dysfunction mediated by NO suppression and increased oxidative stress in penis. The alterations of protein arginine methyltransferases 1 (PRMT1)/dimethylarginine dimethylaminohydrolase (DDAH)/asymmetrical dimethylarginine (ADMA)/NO synthase (NOS) pathway regulate NO production in the vascular endothelium. Epigallocatechin-3-gallate (EGCG) is one of the most abundant and antioxidative ingredients isolated from green tea. In the present study, 40 Sprague-Dawley rats were randomly distributed into four groups: one young rat group and three aged rat groups treated with daily gavage feedings of EGCG at doses of 0, 10 mg kg−1, and 100 mg kg−1 for 12 weeks, respectively. Erectile function was assessed by electrical stimulation of the cavernous nerves with intracavernous pressure (ICP) measurement. After euthanasia, penile tissue was investigated using Western blot and ELISA to assess the PRMT1/DDAH/ADMA/NOS metabolism pathway. Superoxide dismutase (SOD) and malondialdehyde (MDA) levels were detected by colorimetry. We also evaluated smooth muscle contents. The ratio of maximal ICP and mean systemic arterial pressure (MAP) was markedly higher in EGCG-treated aged rats than in untreated aged rats. We found that DDAH1 and DDAH2 were expressed in cavernosal tissue, and they were downregulated in corpora of aged rats. The administration of EGCG upregulated the expression and activity of DDAH. In contrast, EGCG treatment downregulated the expression of PRMT1 and ADMA content. Moreover, EGCG-treated rats showed an improvement in smooth muscle expression, the ratio of smooth muscle cell/collagen fibril, SOD activity, and MDA levels when compared with untreated aged rats.

Toxic Dimethylarginines: Asymmetric Dimethylarginine (ADMA) and Symmetric Dimethylarginine (SDMA)

“…The development of specific PRMT inhibitors, DDAH activators, and AGXT2 activators for ADMA suppression, however, remains a challenging area of research [7,127,128]. Currently, numerous therapies have been shown to reduce ADMA concentrations in a wide range of animal models (Table 3) [110,112,129,130,131,132,133,134,135,136,137,138,139,140,141,142,143,144,145,146,147,148,149,150,151,152,153,154,155,156,157,158,159,160,161,162,163,164,165,166,167,168]. Some of the major approaches include the restoration of the imbalance between l -arginine and ADMA, the regulation of DDAH enzymes and/or activity, and the inhibition of PRMT expression.…”

“…A number of animal studies have furthermore indicated that pioglitazone [131], farnesoid X receptor agonist [132], telmisartan [136], resveratrol [137], melatonin [117,138], atorvastatin [143], shichimotsukokato [144], vitamin E [145], salvianolic acid A [146], N -acetylcysteine [148], oxymatrine [152], metformin [154], epigallocatechin-3-gallate [166], and rosuvastatin [168] can increase the activity and/or expression of DDAHs and thereby reduce ADMA levels. On the other hand, telmisartan [136], glucagon-like peptide-1 receptor agonist [147], epigallocatechin-3-gallate [166], and rosuvastatin [168] may reduce ADMA levels via decreased PRMT-1 expression. However, whether these ADMA-lowering therapies not only reduce circulating ADMA levels but also ADMA levels in target organs requires further clarification.…”

DDAH2 alleviates myocardial fibrosis in diabetic cardiomyopathy through activation of the DDAH/ADMA/NOS/NO pathway in rats

“…Diabetic endothelial dysfunction may arise from the uncoupling of endothelial nitric oxide synthase (eNOS) by forming superoxide anion [O(2)(−)] (16). ADMA, a naturally existing L-arginine analog endogenously synthesized during the methylation of protein arginine residues, is an inhibitor of NOS by competing with L-arginine to bind to the active site of NOS, thus suppressing NO synthesis and causing NOS uncoupling (17). The majority of ADMA can be intracellularly degraded into citrulline and dimethylamine by DDAH (18).…”

Asymmetric Dimethylarginine (ADMA) in Pediatric Renal Diseases: From Pathophysiological Phenomenon to Clinical Biomarker and Beyond

“…On the other hand, epigallocatechin-3-gallate [84], glucagon-like peptide-1 receptor agonist [85], and telmisartan [78] were shown to lower ADMA levels coinciding with downregulation of PRMT-1 expression. The recent discovery of high-resolution crystal structures of DDAH isoforms provides an insight into the molecular mechanisms that regulate their activities [86].…”