Molecular Signaling Mediated by Angiotensin II Type 1A Receptor Blockade Leading to Attenuation of Renal Dysfunction-Associated Heart Failure

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• 作者：Yiwen Li ; Genzou Takemura ; Hideshi Okada ; Shusaku Miyata ; Rumi Maruyama ; Masayasu Esaki ; Hiromitsu Kanamori ; Longhu Li ; Atsushi Ogino ; Takamasa Ohno ; Takehito Kondo ; Munehiro Nakagawa ; Shinya Minatogu
• 关键词：Angiotensin receptors ; Experimental models ; Heart failure ; Renal failure
• 刊名：Journal of Cardiac Failure
• 出版年：2007
• 出版时间：March 2007
• 年：2007
• 卷：13
• 期：2
• 页码：155-162
• 全文大小：655 K

文摘

In patients with end-stage renal disease, angiotensin II type 1A receptor (AT1) blockade attenuates the associated cardiac dysfunction. We investigated the molecular signaling mediating that effect.

Methods and Results

We used 5/6 nephrectomy to induce significant renal dysfunction in AT1 knockout (AT1KO) and wild-type mice (WT). Twelve weeks after nephrectomy, WT showed significant left ventricular dilation and dysfunction that were accompanied by cardiomyocyte hypertrophy, fibrosis, and reduced capillary density. All of these effects were significantly mitigated in AT1KO. Nephrectomy led to upregulation of myocardial expression of AT1, transforming growth factor-β1 (TGF-β1), matrix metalloproteinase (MMP)-2, MMP-9, tissue inhibitor of metalloproteinase-1 (TIMP-1), and phosphorylated Akt (p-Akt), and also led to increased oxidative damage in cardiomyocytes. In AT1KO, TGF-β1, TIMP-1, oxidative damage levels were lower, whereas MMPs and p-Akt levels were higher. Treating nephrectomized WT mice with valsartan (an AT1 blocker), but not hydralazine, improved cardiac function and altered molecular signaling in a manner similar to that seen in AT1KO mice. Notably, AT1 expression was downregulated in valsartan-treated but not hydralazine-treated hearts.

Conclusions

These findings provide novel insight into the mechanism underlying the beneficial effects of AT1 blockade on cardiac function in a model of renal dysfunction–associated heart failure.