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HMG-CoA reductase inhibitors up-regulate anti-aging klotho mRNA via RhoA inactivation in IMCD3 cells.
Cardiovasc Res. 2004 Nov 01; 64(2):331-6.CR

Abstract

OBJECTIVE

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

METHODS AND RESULTS

Klotho mRNA levels were evaluated with real-time RT-PCR. Atorvastatin and pitavastatin increased the expression of klotho mRNA in a dose-dependent manner. This stimulatory effect was abolished by the addition of mevalonate, GGPP and FPP, essential molecules for isoprenylation of the small GTPase Rho. As was the case with the statin treatment, inhibition of Rho-kinase by Y27632 up-regulated klotho mRNA. In contrast to the statin treatment, stimulation with angiotensin II down-regulated klotho mRNA expression without obvious morphological changes. Furthermore, pretreatment with atorvastatin blunted the angiotensin II-induced response and ameliorated the decrease in klotho mRNA expression towards basal levels. RhoA activity was further evaluated by detection of its translocation. Angiotensin II activated RhoA, whereas statins potently inactivated RhoA and blocked RhoA activation by angiotensin II.

CONCLUSION

Statins inactivate the RhoA pathway, resulting in over-expression of klotho mRNA, which may contribute to the novel pleiotropic effects of statins towards vascular protection.

Authors+Show Affiliations

Department of Hypertension and Nephrology, Kyoto Prefectural University School of Medicine, 465 Kajii-cho Kawaramachi Hirokoji, Kyoto 602-8566, Japan. naru1117@koto.kpu-m.ac.jpNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

15485693

Citation

Narumiya, Hiromichi, et al. "HMG-CoA Reductase Inhibitors Up-regulate Anti-aging Klotho mRNA Via RhoA Inactivation in IMCD3 Cells." Cardiovascular Research, vol. 64, no. 2, 2004, pp. 331-6.
Narumiya H, Sasaki S, Kuwahara N, et al. HMG-CoA reductase inhibitors up-regulate anti-aging klotho mRNA via RhoA inactivation in IMCD3 cells. Cardiovasc Res. 2004;64(2):331-6.
Narumiya, H., Sasaki, S., Kuwahara, N., Irie, H., Kusaba, T., Kameyama, H., Tamagaki, K., Hatta, T., Takeda, K., & Matsubara, H. (2004). HMG-CoA reductase inhibitors up-regulate anti-aging klotho mRNA via RhoA inactivation in IMCD3 cells. Cardiovascular Research, 64(2), 331-6.
Narumiya H, et al. HMG-CoA Reductase Inhibitors Up-regulate Anti-aging Klotho mRNA Via RhoA Inactivation in IMCD3 Cells. Cardiovasc Res. 2004 Nov 1;64(2):331-6. PubMed PMID: 15485693.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - HMG-CoA reductase inhibitors up-regulate anti-aging klotho mRNA via RhoA inactivation in IMCD3 cells. AU - Narumiya,Hiromichi, AU - Sasaki,Susumu, AU - Kuwahara,Noriko, AU - Irie,Hidekazu, AU - Kusaba,Tetsuro, AU - Kameyama,Hisako, AU - Tamagaki,Keiichi, AU - Hatta,Tsuguru, AU - Takeda,Kazuo, AU - Matsubara,Hiroaki, PY - 2004/03/05/received PY - 2004/07/15/revised PY - 2004/07/16/accepted PY - 2004/10/16/pubmed PY - 2005/1/11/medline PY - 2004/10/16/entrez SP - 331 EP - 6 JF - Cardiovascular research JO - Cardiovasc Res VL - 64 IS - 2 N2 - OBJECTIVE: Klotho is thought to play a critical role in the development of age-related disorders including arteriosclerosis. Statins may exert vascular protective effects, independent of the lowering of plasma cholesterol levels. We investigated the impact of statins on mRNA expression of the age-suppressor gene, klotho in mIMCD3 cells. METHODS AND RESULTS: Klotho mRNA levels were evaluated with real-time RT-PCR. Atorvastatin and pitavastatin increased the expression of klotho mRNA in a dose-dependent manner. This stimulatory effect was abolished by the addition of mevalonate, GGPP and FPP, essential molecules for isoprenylation of the small GTPase Rho. As was the case with the statin treatment, inhibition of Rho-kinase by Y27632 up-regulated klotho mRNA. In contrast to the statin treatment, stimulation with angiotensin II down-regulated klotho mRNA expression without obvious morphological changes. Furthermore, pretreatment with atorvastatin blunted the angiotensin II-induced response and ameliorated the decrease in klotho mRNA expression towards basal levels. RhoA activity was further evaluated by detection of its translocation. Angiotensin II activated RhoA, whereas statins potently inactivated RhoA and blocked RhoA activation by angiotensin II. CONCLUSION: Statins inactivate the RhoA pathway, resulting in over-expression of klotho mRNA, which may contribute to the novel pleiotropic effects of statins towards vascular protection. SN - 0008-6363 UR - https://www.unboundmedicine.com/medline/citation/15485693/HMG_CoA_reductase_inhibitors_up_regulate_anti_aging_klotho_mRNA_via_RhoA_inactivation_in_IMCD3_cells_ L2 - https://academic.oup.com/cardiovascres/article-lookup/doi/10.1016/j.cardiores.2004.07.011 DB - PRIME DP - Unbound Medicine ER -