Kuwahara Noriko, Sasaki Susumu, Kobara Miyuki, Nakata Tetsuo, Tatsumi Tetsuya, Irie Hidekazu, Narumiya Hiromichi, Hatta Tsuguru, Takeda Kazuo, Matsubara Hiroaki, Hushiki Shinji
Division of Hypertension and Nephrology, Graduate School of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Int J Cardiol. 2008 Jan 11;123(2):84-90. doi: 10.1016/j.ijcard.2007.02.029. Epub 2007 Apr 16.
The klotho gene and its protein product are mainly expressed in the kidney. The klotho protein induces suppression of multiple aging-related phenotypes, and homozygous klotho gene mutant mice display various senescent morbidity. Chronic inhibition of nitric oxide synthase (NOS) induces arteriosclerosis, while HMG-CoA reductase inhibitors (statins) have pleiotropic vascular protective effects besides cholesterol lowering. Therefore, the present studies were performed to determine whether chronic NOS blockade would affect anti-ageing klotho protein expression. In addition, the effects of statins on klotho protein expression and arteriosclerosis in these rats were investigated.
Forty-two rats were divided into 6 groups as follows: (1) control, (2) NOS blockade, (3) atorvastatin (10 mg/kg/day), (4) pitavastatin (3 mg/kg/day), (5) NOS blockade+atorvastatin, (6) NOS blockade+pitavastatin. To induce arteriosclerosis further, a cuff was placed around the left femoral artery in each rat. After 4 weeks observation, rats were killed and renal klotho expression and the level of arteriosclerosis were examined.
The rats of chronic NOS inhibition developed hypertension, while statin treatment did not affect blood pressure in the rats with or without NOS blockade. Despite statin treatment, plasma levels of lipids did not differ among 6 groups. Immunohistochemical staining revealed that klotho protein was localized in the renal tubules. Chronic NOS inhibition markedly reduced renal klotho protein expression, while treatment with atorvastatin or pitavastatin completely prevented the reduction of klotho expression induced by NOS inhibition. In addition, statin treatment significantly improved arteriosclerotic lesions induced by NOS inhibition and cuff placement.
Since statin treatment did not alter blood pressure or serum lipid profiles, a novel vascular protective effect of statins via enhancing anti-aging klotho protein expression is suggested.
klotho基因及其蛋白产物主要在肾脏中表达。klotho蛋白可诱导多种衰老相关表型的抑制，纯合klotho基因突变小鼠表现出各种衰老相关病症。慢性抑制一氧化氮合酶（NOS）可诱发动脉硬化，而HMG-CoA还原酶抑制剂（他汀类药物）除降低胆固醇外还具有多效性血管保护作用。因此，本研究旨在确定慢性NOS阻断是否会影响抗衰老klotho蛋白的表达。此外，还研究了他汀类药物对这些大鼠klotho蛋白表达和动脉硬化的影响。
42只大鼠分为6组如下：（1）对照组，（2）NOS阻断组，（3）阿托伐他汀（10mg/kg/天）组，（4）匹伐他汀（3mg/kg/天）组，（5）NOS阻断+阿托伐他汀组，（6）NOS阻断+匹伐他汀组。为进一步诱发动脉硬化，在每只大鼠的左股动脉周围放置一个袖带。观察4周后，处死大鼠并检测肾脏klotho表达及动脉硬化程度。
慢性NOS抑制的大鼠出现高血压，而他汀类药物治疗对有无NOS阻断的大鼠血压均无影响。尽管进行了他汀类药物治疗，但6组之间的血脂水平并无差异。免疫组织化学染色显示klotho蛋白定位于肾小管。慢性NOS抑制显著降低肾脏klotho蛋白表达，而阿托伐他汀或匹伐他汀治疗完全阻止了NOS抑制诱导的klotho表达降低。此外，他汀类药物治疗显著改善了NOS抑制和袖带放置诱导的动脉硬化病变。
由于他汀类药物治疗未改变血压或血脂谱，提示他汀类药物通过增强抗衰老klotho蛋白表达具有新的血管保护作用。
