FGF2 modulates cardiac remodeling in an isoform- and sex-specific manner.
FGF2 modulates cardiac remodeling in an isoform- and sex-specific manner.
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DOI：
10.1002/phy2.88
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发表时间：
2013-09
影响因子：
2.5
通讯作者：
Doetschman, Tom
中科院分区：
文献类型：
--
作者：
Nusayr, Eyad;Sadideen, Doraid Tarek;Doetschman, Tom
病理性心肌肥大和心肌纤维化是导致心肌机械僵硬和病理生理变化的重塑事件。人类和动物模型都显示出两性二态性，雌性更能免受病理性重塑的影响。成纤维细胞生长因子2 （FGF2）介导心脏肥大、心脏纤维化和心脏损伤保护，具有高分子量和低分子量亚型（分别为Hi FGF2和Lo FGF2）。虽然在心脏病理生理中对异构体特异性功能有一定的了解，但它们在病理性心脏重塑中的作用尚未确定。我们检验了Lo FGF2和Hi FGF2以同种异型特异性方式调节病理性心脏重构的假设。混合背景的年轻成年雄性和雌性小鼠，年龄在8至12周龄之间，缺乏Hi FGF2或Lo FGF2（分别为Hi KO或Lo KO），每天注射异丙肾上腺素（Iso） 4天，之后将其心脏与野生型组进行比较。经iso治疗后，女性Lo - KO心脏在肥厚和纤维化反应方面没有显著差异，而女性Hi - KO心脏则表现出迟钝的肥厚反应。在雄性动物中，Lo - KO心脏表现为纤维化反应加剧，α-平滑肌肌动蛋白表达增加，而Hi - KO心脏表现为纤维化反应减弱，心房利钠因子蛋白表达增加。因此，在雌性心脏中，Hi - FGF2介导心脏肥厚，而在雄性心脏中，Lo - FGF2和Hi - FGF2在心脏纤维化中表现为相反的作用，Lo - FGF2具有保护作用，而Hi - FGF2具有损害作用。总之，儿茶酚胺过度激活后的心脏重构由FGF2以同种异构体和性别特异性的方式调节。
Pathological cardiac hypertrophy and cardiac fibrosis are remodeling events that result in mechanical stiffness and pathophysiological changes in the myocardium. Both humans and animal models display a sexual dimorphism where females are more protected from pathological remodeling. Fibroblast growth factor 2 (FGF2) mediates cardiac hypertrophy, cardiac fibrosis, and protection against cardiac injury, and is made in high molecular weight and low molecular weight isoforms (Hi FGF2 and Lo FGF2, respectively). Although some light has been shed on isoform-specific functions in cardiac pathophysiology, their roles in pathologic cardiac remodeling have yet to be determined. We tested the hypothesis that Lo FGF2 and Hi FGF2 modulate pathological cardiac remodeling in an isoform-specific manner. Young adult male and female mice between 8 and 12 weeks of age of mixed background that were deficient in either Hi FGF2 or Lo FGF2 (Hi KO or Lo KO, respectively) were subjected to daily injections of isoproterenol (Iso) for 4 days after which their hearts were compared to wild-type cohorts. Post-Iso treatment, female Lo KO hearts do not exhibit significant differences in their hypertrophic and fibrotic response, whereas female Hi KO hearts present with a blunted hypertrophic response. In male animals, Lo KO hearts present with an exacerbated fibrotic response and increased α-smooth muscle actin protein expression, whereas Hi KO hearts present with a blunted fibrotic response and increased atrial natriuretic factor protein expression Thus, in female hearts Hi FGF2 mediates cardiac hypertrophy, whereas in male hearts Lo FGF2 and Hi FGF2 display an antithetical role in cardiac fibrosis where Lo FGF2 is protective while Hi FGF2 is damaging. In conclusion, cardiac remodeling following catecholamine overactivation is modulated by FGF2 in isoform- and sex-specific manners.