Wakino Shu, Hayashi Koichi, Tatematsu Satoru, Hasegawa Kazuhiro, Takamatsu Ichiro, Kanda Takeshi, Homma Koichiro, Yoshioka Kyoko, Sugano Naoki, Saruta Takao
Department of Internal Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
Hypertens Res. 2005 Mar;28(3):255-62. doi: 10.1291/hypres.28.255.
Peroxisome proliferator activated receptor-gamma (PPARgamma) ligands increase nitric oxide (NO) production and reduce systemic blood pressure. Asymmetric dimethylarginine (ADMA) is an endogenous nitric oxide synthase (NOS) inhibitor degraded by the enzyme dimethylarginine dimethylaminohydrolase (DDAH), which has two isoforms, DDAH-I and -II. In order to elucidate the mechanism whereby PPARgamma ligands affect NO metabolism, their effects on the DDAH-ADMA pathway were investigated. Six-week-old male Wister-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) were maintained with or without pioglitazone (PIO), a PPARgamma ligand. After 4 weeks, serum ADMA levels and urinary daily NO excretion were analyzed. Tissue DDAH expression was examined by real-time polymerase chain reaction (PCR), immunoblotting, and immunohistochemistry. The results showed that PIO decreased serum ADMA and increased urinary NO excretion in both WKY and SHR. Also in both strains, the expression level of DDAH-II in the kidney was increased at transcriptional levels, although the DDAH-I level was unaffected. PIO lowered blood pressure in SHR, but not in WKY. We also demonstrated that PIO induced DDAH-II protein expression in Marbin-Dubin Canine Kidney (MDCK) cells, a renal tubular cell line. In conclusion, a PPARgamma ligand was here found to increase NO production partly by upregulating tissue DDAH-II expression and decreasing systemic ADMA levels. This mechanism constitutes a direct action on renal tubular cells, but is less likely to be responsible for the blood pressure-lowering effects of PPARgamma ligands. Since ADMA is one of the risk factors for cardiovascular events, this study provides compelling evidence that PPARgamma ligands have the potential for reducing cardiovascular risks.
过氧化物酶体增殖物激活受体γ（PPARγ）配体可增加一氧化氮（NO）的生成并降低全身血压。不对称二甲基精氨酸（ADMA）是一种内源性一氧化氮合酶（NOS）抑制剂，可被二甲基精氨酸二甲胺水解酶（DDAH）降解，该酶有两种同工型，即DDAH-Ⅰ和DDAH-Ⅱ。为了阐明PPARγ配体影响NO代谢的机制，研究了它们对DDAH-ADMA途径的影响。将6周龄雄性Wistar-Kyoto大鼠（WKY）和自发性高血压大鼠（SHR）分为接受或未接受PPARγ配体吡格列酮（PIO）处理的两组。4周后，分析血清ADMA水平和尿中每日NO排泄量。通过实时聚合酶链反应（PCR）、免疫印迹和免疫组织化学检测组织DDAH表达。结果显示，PIO可降低WKY和SHR的血清ADMA水平并增加尿中NO排泄量。在这两种品系中，尽管DDAH-Ⅰ水平未受影响，但肾脏中DDAH-Ⅱ的表达水平在转录水平上有所增加。PIO可降低SHR的血压，但对WKY无效。我们还证明，PIO可诱导肾小管细胞系马-杜氏犬肾（MDCK）细胞中DDAH-Ⅱ蛋白表达。总之，本研究发现PPARγ配体可通过上调组织DDAH-Ⅱ表达和降低全身ADMA水平来部分增加NO生成。该机制构成了对肾小管细胞的直接作用，但不太可能是PPARγ配体降压作用的原因。由于ADMA是心血管事件的危险因素之一，本研究提供了令人信服的证据，表明PPARγ配体具有降低心血管风险的潜力。
