HMG-CoA reductase inhibition improves anti-aging klotho protein expression and arteriosclerosis in rats with chronic inhibition of nitric oxide synthesis

Kuwahara, Noriko; Sasaki, Susumu; Kobara, Miyuki; Nakata, Tetsuo; Tatsumi, Tomohide; Irie, Hidekazu; Narumiya, Hiromichi; Hatta, Tsuguru; Takeda, Kazuo; Matsubara, Hiroaki; Hushiki, Shinji

doi:10.1016/j.ijcard.2007.02.029

Cited by 54 publications

(48 citation statements)

References 25 publications

(30 reference statements)

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“…Statin therapy is associated with improvements in endothelial function, and newer agents such as pitavastatin have shown promise in promoting eNOS activity/signaling, 18, 57 anti-senescence factors, 18, 58 and improved collateral-dependent perfusion in CAD 59 and acute ischemic stroke. 60 Because our current and previous results 8,9 implicate decreased eNOS activity/vascular senescence in CVRF-associated collateral rarefaction, we tested pitavastatin administration in hypertensive mice from 1.5-to-8 months-age.…”

Section: Discussionmentioning

confidence: 99%

Cardiovascular risk factors cause premature rarefaction of the collateral circulation and greater ischemic tissue injury

et al. 2015

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Rationale Collaterals lessen tissue injury in occlusive disease. However, aging causes progressive decline in their number and smaller diameters in those that remain (collateral rarefaction), beginning at 16 months-age in mice (ie, middle age), and worse ischemic injury—effects that are accelerated in even 3 months-old eNOS−/− mice. These findings have found indirect support in recent human studies. Objective We sought to determine if other cardiovascular risk factors (CVRFs) associated with endothelial dysfunction cause collateral rarefaction, investigate possible mechanisms, and test strategies for prevention. Methods and Results Mice with nine different models of CVRFs of 4–12 months-age were assessed for number and diameter of native collaterals in skeletal muscle and brain, and for collateral-dependent perfusion and ischemic injury after arterial occlusion. Hypertension caused collateral rarefaction whose severity increased with duration and level of hypertension, accompanied by greater hindlimb ischemia and cerebral infarct volume. Chronic treatment of wildtype mice with L-NG-nitro-arginine methylester caused similar rarefaction and worse ischemic injury that were not prevented by lowering arterial pressure with hydralazine. Metabolic syndrome, hypercholesterolemia, diabetes mellitus, and obesity also caused collateral rarefaction. Neither chronic statin treatment nor exercise training lessened hypertension-induced rarefaction. Conclusion Chronic CVRF presence caused collateral rarefaction and worse ischemic injury, even at relatively young ages. Rarefaction was associated with increased proliferation rate of collateral endothelial cells, effects that may promote accelerated endothelial cell senescence.

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Section: Discussionmentioning

confidence: 99%

Cardiovascular risk factors cause premature rarefaction of the collateral circulation and greater ischemic tissue injury

et al. 2015

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“…Until now, there have been few reports showing that statins upregulate klotho expression. Statins were shown to upregulate klotho mRNA expression via RhoA inactivation in mouse internal medulla collecting duct epithelial cells [29] and to upregulate klotho protein expression and improve arteriosclerosis in rats with chronic inhibition of nitric oxide synthesis [30]. In this study, we focused on the association of statin and klotho expression in CsA-induced renal injury based on the antioxidant property of statins.…”

Section: Discussionmentioning

confidence: 99%

Statin Upregulates the Expression of <b><i>Klotho</i></b>, an Anti-Aging Gene, in Experimental Cyclosporine Nephropathy

Yoon

Lim

Piao

et al. 2012

Nephron Exp Nephrol

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Background: We recently reported that long-term cyclosporine (CsA)-induced oxidative stress is associated with decreased expression of klotho, an anti-aging gene. This study evaluated whether the antioxidant effect of statin might upregulate klotho expression in CsA-induced renal injury. Methods: Two separate experiments were performed. First, the dose-dependent effect of statin on klotho expression was evaluated in normal mouse kidneys. Second, the effect of statin on klotho expression was evaluated in experimental chronic CsA nephropathy in mice. We performed immunohistochemistry and immunoblotting for klotho, Forkhead box O transcription factors [FoxOs; phosphorylated FoxO1 (p-FoxO1) and FoxO3a (p-FoxO3a)] and their target molecules, manganese superoxide dismutase (MnSOD), Bim and hemeoxygenase-1. Results: Statin treatment upregulated klotho expression in a dose-dependent manner in the normal mouse kidney and alleviated the decrease in klotho expression in kidneys exhibiting CsA nephropathy. CsA administration increased p-FoxO1 expression and decreased p-FoxO3a expression, whereas concurrent statin treatment reversed these changes, increased the expression of the antioxidant enzymes MnSOD and hemeoxygenase-1 and decreased the expression of the pro-apoptotic protein Bim. Conclusion: Statin-mediated upregulation of klotho expression and differential regulation of FoxO expression promote resistance to CsA-induced oxidative stress.

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“…119 A HMG CoA reductase inhibitor, cerivastatin, enhances angiogenesis and restores the impaired neovascularization in Kl +/− mice after ischemic lind limb illustrated by similar blood perfusion between Kl +/− mice treated with cerivastatin and WT mice. 118 The mechanism by which statins accelerate angiogenesis and vasculogenesis in Klotho-deficient mice is at least partly related to maintenance of Klotho, 181,224 and secondary to improvement of endothelial function through endothelium-derived NO production. 117 …”

Section: Potential Strategies To Increase Klotho Proteinmentioning

confidence: 99%

Secreted Klotho and Chronic Kidney Disease

Kuro‐o

Moe

2012

Advances in Experimental Medicine and Biology

111

102

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Soluble Klotho (sKl) in the circulation can be generated directly by alterative splicing of the Klotho transcript or the extracellular domain of membrane Klotho can be released from membrane-anchored Klotho on the cell surface. Unlike membrane Klotho which functions as a coreceptor for fibroblast growth factor-23 (FGF23), sKl, acts as hormonal factor and plays important roles in anti-aging, anti-oxidation, modulation of ion transport, and Wnt signaling. Emerging evidence reveals that Klotho deficiency is an early biomarker for chronic kidney diseases as well as a pathogenic factor. Klotho deficiency is associated with progression and chronic complications in chronic kidney disease including vascular calcification, cardiac hypertrophy, and secondary hyperparathyroidism. In multiple experimental models, replacement of sKl, or manipulated up-regulation of endogenous Klotho protect the kidney from renal insults, preserve kidney function, and suppress renal fibrosis, in chronic kidney disease. Klotho is a highly promising candidate on the horizon as an early biomarker, and as a novel therapeutic agent for chronic kidney disease.

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HMG-CoA reductase inhibition improves anti-aging klotho protein expression and arteriosclerosis in rats with chronic inhibition of nitric oxide synthesis

Cited by 54 publications

References 25 publications

Cardiovascular risk factors cause premature rarefaction of the collateral circulation and greater ischemic tissue injury

Cardiovascular risk factors cause premature rarefaction of the collateral circulation and greater ischemic tissue injury

Statin Upregulates the Expression of <b><i>Klotho</i></b>, an Anti-Aging Gene, in Experimental Cyclosporine Nephropathy

Secreted Klotho and Chronic Kidney Disease

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