Deficiency in the anti-aging gene Klotho promotes aortic valve fibrosis through AMPKα-mediated activation of RUNX2.
Deficiency in the anti-aging gene Klotho promotes aortic valve fibrosis through AMPKα-mediated activation of RUNX2.
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作者：
Chen J;Lin Y;Sun Z
纤维化主动脉瓣疾病（FAVD）是导致主动脉瓣狭窄的重要原因，但由于其病因不明，目前尚无有效的治疗方法。本研究的目的是研究抗衰老Klotho基因（KL）的缺陷是否会促进高脂饮食诱导的FAVD，并探索潜在的分子机制。杂合子Klotho缺陷型（KL +/−）小鼠和WT同窝小鼠喂食高脂饲料（HFD）或正常饲料13周，然后再用AMPKα激活剂（AICAR）处理2周。与WT小鼠相比，HFD导致KL +/−小鼠主动脉瓣中胶原蛋白水平增加更大，表明Klotho缺乏促进HFD诱导的主动脉瓣纤维化（AVF）。在喂食HFD的KL +/−小鼠的主动脉瓣中，AMPKα活性（pAMPKα）降低，而胶原蛋白I和RUNX 2的蛋白表达增加。在KL +/−小鼠中，AICAR治疗显著减弱了HFD诱导的AVF。AICAR不仅消除了pAMPKα的下调，还消除了喂食HFD的KL +/−小鼠主动脉瓣中胶原I和RUNX 2的上调。在培养的猪主动脉瓣间质细胞中，Klotho缺陷血清加胆固醇增加了RUNX 2和胶原蛋白I的表达，这是由AICAR激活AMPKα减弱。有趣的是，RUNX 2的沉默消除了Klotho缺乏对胆固醇诱导的基质蛋白（包括胶原蛋白I和骨钙素）上调的刺激作用。总之，Klotho基因缺陷促进HFD诱导的主动脉瓣纤维化，可能通过AMPKα-RUNX 2途径。
Fibrotic aortic valve disease (FAVD) is an important cause of aortic stenosis, yet currently there is no effective treatment for FAVD due to its unknown etiology. The purpose of this study was to investigate whether deficiency in the anti‐aging Klotho gene (KL) promotes high‐fat‐diet‐induced FAVD and to explore the underlying molecular mechanism. Heterozygous Klotho‐deficient (KL +/−) mice and WT littermates were fed with a high‐fat diet (HFD) or normal diet for 13 weeks, followed by treatment with the AMPKα activator (AICAR) for an additional 2 weeks. A HFD caused a greater increase in collagen levels in the aortic valves of KL +/− mice than of WT mice, indicating that Klotho deficiency promotes HFD‐induced aortic valve fibrosis (AVF). AMPKα activity (pAMPKα) was decreased, while protein expression of collagen I and RUNX2 was increased in the aortic valves of KL +/− mice fed with a HFD. Treatment with AICAR markedly attenuated HFD‐induced AVF in KL +/− mice. AICAR not only abolished the downregulation of pAMPKα but also eliminated the upregulation of collagen I and RUNX2 in the aortic valves of KL +/− mice fed with HFD. In cultured porcine aortic valve interstitial cells, Klotho‐deficient serum plus cholesterol increased RUNX2 and collagen I protein expression, which were attenuated by activation of AMPKα by AICAR. Interestingly, silencing of RUNX2 abolished the stimulatory effect of Klotho deficiency on cholesterol‐induced upregulation of matrix proteins, including collagen I and osteocalcin. In conclusion, Klotho gene deficiency promotes HFD‐induced fibrosis in aortic valves, likely through the AMPKα–RUNX2 pathway.
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影响因子：
37.8
作者：
Go AS;Mozaffarian D;Roger VL;Benjamin EJ;Berry JD;Blaha MJ;Dai S;Ford ES;Fox CS;Franco S;Fullerton HJ;Gillespie C;Hailpern SM;Heit JA;Howard VJ;Huffman MD;Judd SE;Kissela BM;Kittner SJ;Lackland DT;Lichtman JH;Lisabeth LD;Mackey RH;Magid DJ;Marcus GM;Marelli A;Matchar DB;McGuire DK;Mohler ER 3rd;Moy CS;Mussolino ME;Neumar RW;Nichol G;Pandey DK;Paynter NP;Reeves MJ;Sorlie PD;Stein J;Towfighi A;Turan TN;Virani SS;Wong ND;Woo D;Turner MB;American Heart Association Statistics Committee and Stroke Statistics Subcommittee
通讯作者：
American Heart Association Statistics Committee and Stroke Statistics Subcommittee
DOI：
10.1161/hypertensionaha.114.03791
发表时间：
2014-11
期刊：
Hypertension (Dallas, Tex. : 1979)
影响因子：
--
作者：
Crosswhite P;Chen K;Sun Z
通讯作者：
Sun Z
DOI：
10.1016/0735-1097(93)90249-z
发表时间：
1993-04-01
影响因子：
24
作者：
LINDROOS, M;KUPARI, M;TILVIS, R
通讯作者：
TILVIS, R
影响因子：
64.5
作者：
Lee, Na Kyung;Sowa, Hideaki;Karsenty, Gerard
通讯作者：
Karsenty, Gerard
影响因子：
158.5
作者：
Cowell, SJ;Newby, DE;Boon, NA
通讯作者：
Boon, NA