Transverse aortic constriction leads to accelerated heart failure in mice lacking PPAR-γ coactivator 1α
Transverse aortic constriction leads to accelerated heart failure in mice lacking PPAR-γ coactivator 1α
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DOI：
10.1073/pnas.0603615103
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发表时间：
2006-06-27
影响因子：
11.1
通讯作者：
Spiegelman, Bruce M.
中科院分区：
文献类型：
--
作者：
Arany, Zoltan;Novikov, Mikhail;Spiegelman, Bruce M.
心力衰竭伴有重要的代谢缺陷。转录辅激活因子过氧化物酶体增殖物激活受体 -γ辅激活因子1α（PGC - 1α）是线粒体生物学和代谢的强大调节因子。在心脏应激模型中，如由横向主动脉缩窄（TAC）所产生的模型中，PGC - 1α以及许多受PGC - 1α调控的基因受到抑制。这一发现表明，PGC - 1α的抑制可能导致心脏对慢性血流动力学负荷的适应不良反应。我们在此表明，在基因工程改造为缺乏PGC - 1α的小鼠中，TAC会导致心脏功能障碍加速，并伴有明显的临床心力衰竭迹象。用儿茶酚胺肾上腺素处理组织培养中的心脏细胞会导致PGC - 1α及其许多靶基因的抑制，重现了体内对TAC的反应结果。重要的是，引入异位的PGC - 1α可以逆转肾上腺素对这些基因中大多数基因的抑制。总之，这些数据表明内源性PGC - 1α具有心脏保护功能，并表明PGC - 1α的抑制对心力衰竭的发展有重要作用。此外，这些数据表明提高PGC - 1α的活性可能在心力衰竭的治疗中具有治疗潜力。
Heart failure is accompanied by important defects in metabolism. The transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1 alpha) is a powerful regulator of mitochondrial biology and metabolism. PGC-1 alpha and numerous genes regulated by PGC-1 alpha are repressed in models of cardiac stress, such as that generated by transverse aortic constriction (TAC). This finding has suggested that PGC-1 alpha repression may contribute to the maladaptive response of the heart to chronic hemodynamic loads. We show here that TAC in mice genetically engineered to lack PGC-1 alpha leads to accelerated cardiac dysfunction, which is accompanied by signs of significant clinical heart failure. Treating cardiac cells in tissue culture with the catecholamine epinephrine leads to repression of PGC-1a and many of its target genes, recapitulating the findings in vivo in response to TAC. Importantly, introduction of ectopic PGC-1 alpha can reverse the repression of most of these genes by epinephrine. Together, these data indicate that endogenous PGC-1 alpha serves a cardioprotective function and suggest that repression of PGC-1 alpha significantly contributes to the development of heart failure. Moreover, the data suggest that elevating PGC-1 alpha activity may have therapeutic potential in the treatment of heart failure.