HMG-CoA reductase inhibitors up-regulate anti-aging klotho mRNA via RhoA inactivation in IMCD3 cells

doi:10.1016/j.cardiores.2004.07.011

Cardiovascular Research 2004 64(2):331-336; doi:10.1016/j.cardiores.2004.07.011
© 2004 by European Society of Cardiology

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HMG-CoA reductase inhibitors up-regulate anti-aging klotho mRNA via RhoA inactivation in IMCD3 cells

Hiromichi Narumiya^a^,*, Susumu Sasaki^a, Noriko Kuwahara^a, Hidekazu Irie^a, Tetsuro Kusaba^a, Hisako Kameyama^a, Keiichi Tamagaki^a, Tsuguru Hatta^a, Kazuo Takeda^a and Hiroaki Matsubara^b

^aDepartment of Hypertension and Nephrology, Kyoto Prefectural University School of Medicine, 465 Kajii-cho Kawaramachi Hirokoji, Kyoto 602-8566, Japan
^bDepartment of Cardiology and Vascular Regenerative Medicine, Kyoto Prefectural University School of Medicine, Kyoto, Japan

^* Corresponding author. Tel.: +81 75 251 5511; fax: +81 75 251 5514. Email address: naru1117{at}koto.kpu-m.ac.jp

Objective: Klotho is thought to play a critical role in thedevelopment of age-related disorders including arteriosclerosis.Statins may exert vascular protective effects, independent ofthe lowering of plasma cholesterol levels. We investigated theimpact of statins on mRNA expression of the age-suppressor gene,klotho in mIMCD3 cells.

Methods and results: Klotho mRNA levels were evaluated withreal-time RT-PCR. Atorvastatin and pitavastatin increased theexpression of klotho mRNA in a dose-dependent manner. This stimulatoryeffect was abolished by the addition of mevalonate, GGPP andFPP, essential molecules for isoprenylation of the small GTPaseRho. As was the case with the statin treatment, inhibition ofRho-kinase by Y27632 up-regulated klotho mRNA. In contrast tothe statin treatment, stimulation with angiotensin II down-regulatedklotho mRNA expression without obvious morphological changes.Furthermore, pretreatment with atorvastatin blunted the angiotensinII-induced response and ameliorated the decrease in klotho mRNAexpression towards basal levels. RhoA activity was further evaluatedby detection of its translocation. Angiotensin II activatedRhoA, whereas statins potently inactivated RhoA and blockedRhoA activation by angiotensin II.

Conclusion: Statins inactivate the RhoA pathway, resulting inover-expression of klotho mRNA, which may contribute to thenovel pleiotropic effects of statins towards vascular protection.

KEYWORDS HMG-CoA reductase inhibitors; Klotho; RhoA; Real-time RT-PCR

Time for primary review 20 days

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