TY - JOUR
T1 - In vivo klotho gene delivery protects against endothelial dysfunction in multiple risk factor syndrome
AU - Saito, Yuichiro
AU - Nakamura, Tetsuya
AU - Ohyama, Yoshio
AU - Suzuki, Toru
AU - Iida, Akihiro
AU - Shiraki-Iida, Takako
AU - Kuro-o, Makoto
AU - Nabeshima, Yo ichi
AU - Kurabayashi, Masahiko
AU - Nagai, Ryozo
N1 - Funding Information:
We thank S. Saiki, Y. Nonaka and M. Yamazaki for technical and secretarial assistance. This study was supported by the Program for Promotion of Fundamental Studies in Health Sciences of the Organization for Drug ADR Relief, R&D Promotion and Product Review of Japan (R.N.); Kimura Memorial Heart Foundation Grant for Research on Autonomic Nervous System and Hypertension; Japan Heart Foundation Grant for Study Group of Molecular Cardiology; Japan Heart Foundation Grant for Research on Hypertension and Vascular Metabolism; and Japan Heart Foundation/Pfizer Grant for Cardiovascular Disease Research and Research Foundation for Cancer and Cardiovascular Diseases (Y.S.).
PY - 2000/9/24
Y1 - 2000/9/24
N2 - The klotho gene, originally identified by insertional mutagenesis in mice, suppresses multiple aging phenotypes (e.g., arteriosclerosis, pulmonary emphysema, osteoporosis, infertility, and short life span). We have previously shown that mice heterozygous for a defect in the klotho gene upon parabiosis with wild-type mice show improved endothelial function, suggesting that the klotho gene product protects against endothelial dysfunction. In the present 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 adenovirus-mediated klotho gene delivery can (1) ameliorate vascular endothelial dysfunction, (2) increase nitric oxide production, (3) reduce elevated blood pressure, and (4) prevent medial hypertrophy and perivascular fibrosis. Based on these findings, klotho gene delivery improves endothelial dysfunction through a pathway involving nitric oxide, and is involved in modulating vascular function (e.g., hypertension and vascular remodeling). Our findings establish the basis for the therapeutic potential of klotho gene delivery in atherosclerotic disease. (C) 2000 Academic Press.
AB - The klotho gene, originally identified by insertional mutagenesis in mice, suppresses multiple aging phenotypes (e.g., arteriosclerosis, pulmonary emphysema, osteoporosis, infertility, and short life span). We have previously shown that mice heterozygous for a defect in the klotho gene upon parabiosis with wild-type mice show improved endothelial function, suggesting that the klotho gene product protects against endothelial dysfunction. In the present 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 adenovirus-mediated klotho gene delivery can (1) ameliorate vascular endothelial dysfunction, (2) increase nitric oxide production, (3) reduce elevated blood pressure, and (4) prevent medial hypertrophy and perivascular fibrosis. Based on these findings, klotho gene delivery improves endothelial dysfunction through a pathway involving nitric oxide, and is involved in modulating vascular function (e.g., hypertension and vascular remodeling). Our findings establish the basis for the therapeutic potential of klotho gene delivery in atherosclerotic disease. (C) 2000 Academic Press.
KW - Atherosclerosis
KW - Diabetes mellitus
KW - Endothelium
KW - Gene therapy
KW - Hyperlipidemia
KW - Hypertension
KW - Klotho
KW - Nitric oxide
KW - Obesity
KW - Vascular remodeling
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U2 - 10.1006/bbrc.2000.3470
DO - 10.1006/bbrc.2000.3470
M3 - Article
C2 - 11027545
AN - SCOPUS:0034710838
SN - 0006-291X
VL - 276
SP - 767
EP - 772
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 2
ER -