Follistatin like 1 Regulates Hypertrophy in Heart Failure with Preserved Ejection Fraction.
Follistatin like 1 Regulates Hypertrophy in Heart Failure with Preserved Ejection Fraction.
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DOI：
10.1016/j.jacbts.2016.04.002
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发表时间：
2016-06
期刊：
影响因子：
--
通讯作者：
Sam F
中科院分区：
文献类型：
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作者：
Tanaka K;Valero-Muñoz M;Wilson RM;Essick EE;Fowler CT;Nakamura K;van den Hoff M;Ouchi N;Sam F
射血分数正常的心力衰竭（HFpEF）占所有心力衰竭（HF）临床表现的约50%，预计其患病率将增加。然而，目前尚无针对HFpEF的循证治疗;因此，HFpEF是一个主要的未满足需求。虽然高血压是HFpEF的最重要的单一风险因素，临床试验和人类HF登记研究的患病率为60%至89%，但单独的血压治疗不足以预防和治疗HFpEF。卵泡抑素样1（Fstl 1），细胞外糖蛋白卵泡抑素家族的一个分支成员，先前已被证明在HF中升高，射血分数降低，并与左心室质量增加相关。在这项研究中，HFpEF患者的Fstl 1血液水平升高。这种增加在高血压诱导的HFpEF小鼠和醛固酮刺激的成年大鼠心室肌细胞中也很明显。用重组Fstl 1治疗废除了醛固酮诱导的心肌细胞肥大，表明Fstl 1在HFpEF中调节肥大的作用。E/A比值也有所降低，这是舒张功能障碍的一个指标。此外，在特异性消融心肌细胞中Fstl 1的小鼠模型（心肌细胞特异性Fstl 1敲除[cFstl 1-KO]）中诱导的HFpEF显示HFpEF恶化，舒张功能障碍恶化。此外，cFstl 1-KO-HFpEF小鼠表现出更明显的心肌细胞肥大，心房利钠肽和脑利钠肽表达的分子标志物增加。这些结果表明，Fstl 1发挥治疗作用，通过调节心脏肥大HFpEF。Fstl 1，也称为转化生长因子-β刺激的克隆36，是一种与心脏疾病的病理生理学有关的细胞外糖蛋白。相对于其他卵泡抑素家族成员，Fstl 1以非规范的方式起作用，但其功能仍知之甚少。慢性稳定型HFpEF患者的循环Flst 1水平升高。fstl 1治疗调节体外和体内心肌细胞肥大。小鼠心肌细胞Fstl 1缺失导致HFpEF表型。这些研究表明，Fstl 1可能是治疗HFpEF通过调节心脏肥大和改善舒张功能障碍的参数有效。
Heart failure with preserved ejection fraction (HFpEF) accounts for ∼50% of all clinical presentations of heart failure, (HF) and its prevalence is expected to increase. However, there are no evidence-based therapies for HFpEF; thus, HFpEF represents a major unmet need. Although hypertension is the single most important risk factor for HFpEF, with a prevalence of 60% to 89% from clinical trials and human HF registries, blood pressure therapy alone is insufficient to prevent and treat HFpEF. Follistatin-like 1 (Fstl1), a divergent member of the follistatin family of extracellular glycoproteins, has previously been shown to be elevated in HF with reduced ejection fraction and associated with increased left ventricular mass. In this study, blood levels of Fstl1 were increased in humans with HFpEF. This increase was also evident in mice with hypertension-induced HFpEF and adult rat ventricular myocytes stimulated with aldosterone. Treatment with recombinant Fstl1 abrogated aldosterone-induced cardiac myocyte hypertrophy, suggesting a role for Fstl1 in the regulation of hypertrophy in HFpEF. There was also a reduction in the E/A ratio, a measure of diastolic dysfunction. Furthermore, HFpEF induced in a mouse model that specifically ablates Fstl1 in cardiac myocytes (cardiac myocyte-specific Fstl1 knockout [cFstl1-KO]) showed exacerbation of HFpEF with worsened diastolic dysfunction. In addition, cFstl1-KO-HFpEF mice demonstrated more marked cardiac myocyte hypertrophy with increased molecular markers of atrial natriuretic peptide and brain natriuretic peptide expression. These findings indicate that Fstl1 exerts therapeutic effects by modulating cardiac hypertrophy in HFpEF. Fstl1, also known as transforming growth factor-β–stimulated clone 36, is an extra-cellular glycoprotein implicated in the pathophysiology of cardiac disease. Fstl1 acts in a noncanonical manner relative to other follistatin family members, but its functions remain poorly understood. Circulating Flst1 levels are increased in humans with chronic stable HFpEF. Fstl1 treatment modulates cardiomyocyte hypertrophy in vitro and in vivo. Cardiac myocyte deletion of Fstl1 worsens the HFpEF phenotype in mice. These studies indicate that Fstl1 may be therapeutically effective in HFpEF by modulating cardiac hypertrophy and improving parameters of diastolic dysfunction.