Klotho, atherosclerosis

Disruption of klotho gene expression causes multiple aging phenotypes including arteriosclerosis, pulmonary emphysema, osteoporosis, infertility, and skin atrophy. Although klotho supplementation has been shown to improve the aging phenotype of klotho deficient mice which as would be expected , it remained to be addressed whether klotho supplementation in a heterogeneous experimental animal of vascular dysfunction would improve vascular function which is a prerequisite to address the generality of the effects of klotho on the vasculature.klotho gene transfer improves endothelial function and increases NO metabolites strongly suggests a direct and possibly cooperative regulatory pathway between NO and klotho in the vasculature. Equally important is the finding that klotho gene expression improved blood pressure and induced vascular remodeling.

These findings strongly suggest an underlying role of the klotho gene product in the regulation of endothelial function and of atherosclerosis. Vasodilatation induced by endothelium-derived NO has been reported to be impaired in hypertension , diabetes mellitus and hyperlipidemia . These observations lead to the hypothesis that a decrease in the klotho gene expression may be atherogenic due to direct or indirect involvement with reduced NO production in these common diseases. findings collectively show a coupling between klotho gene expression and NO as a general phenomenon in vascular diseased states which establishes and confirms a regulatory interactive pathway between NO and klotho in the vasculature. Although the cellular and molecular mechanisms of the relationship between klotho and regulation of NO need to be clarified in further studies, involvement of the klotho gene in decreased NO formation by down-regulated eNOS or accelerated degeneration of NO by NO scavenger such as superoxide anion are plausible regulatory pathways.

Another interesting finding is that klotho gene transfer significantly prevented perivascular fibrosis in the coronary arteries as chronic inhibition of NOS with L-NAME has been reported to be associated with an increase in wall thickening and coronary perivascular fibrosis in the rat heart. These histological findings also further support an association between NO and klotho. NO and klotho, although speculation, an increase in systemic NO production may be involved in reduction in medial hypertrophy of aorta and coronary perivascular fibrosis.Some studies indicate that supplementation of the klotho gene restores endothelial-dependent aortic dilatation and accelerates systemic NO production, resulting in a decrease in blood pressure and vascular remodeling. klotho gene therapy is a potentially viable and novel therapeutic strategy for preventive treatment of atherosclerotic cardiovascular diseases.
Vol. 276, No. 2, 2000 BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS