In vivo klotho gene delivery protects against endothelial dysfunction in multiple risk factor syndrome

The klotho gene, originally identified by insertional mutagenesis in mice, suppresses multiple aging phenotypes (e.g., arteriosclerosis, pulmonary emp hysema, osteoporosis, infertility, and short life span). We have previously shown that mice heterozygous for a defect in the klotho gene upon parabios is with wild-type mice show improved endothelial function, suggesting that the klotho gene product protects against endothelial dysfunction. In the pr esent study, using the Otsuka Long-Evans Tokushima Fatty (OLETF) rat which demonstrates multiple atherogenic risk factors (e.g, hypertension, obesity, severe hyperglycemia, and hypertriglyceridemia) and is thus considered an experimental animal model of atherosclerotic disease, we show that adenovir us-mediated klotho gene delivery can (1) ameliorate vascular endothelial dy sfunction, (2) increase nitric oxide production, (3) reduce elevated blood pressure, and (4) prevent medial hypertrophy and perivascular fibrosis. Bas ed on these findings, klotho gene delivery improves endothelial dysfunction through a pathway involving nitric oxide, and is involved in modulating va scular function (e.g,, hypertension and vascular remodeling). Our findings establish the basis for the therapeutic potential of klotho gene delivery i n atherosclerotic disease. (C) 2000 Academic Press.