Chunhacha Preedakorn, Pinkaew Decha, Sinthujaroen Patuma, Bowles Dawn E, Fujise Ken
Division of Cardiology, Department of Medicine, University of Washington, Seattle, WA, 98109, USA.
Department of Biochemistry and Microbiology, and Cell-based Drug and Health Product Development Research Unit (CDD), Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, 10330, Thailand.
Cell Death Discov. 2021 Oct 23;7(1):310. doi: 10.1038/s41420-021-00692-w.
Heart failure (HF) has reached epidemic proportions in developed countries, affecting over 20 million people worldwide. Despite modern medical and device therapies, 60-70% of HF patients still die within 5 years of diagnosis as it relentlessly progresses through pervasive apoptotic loss of cardiomyocytes. Although fortilin, a 172-amino-acid anti-p53 molecule, is one of the most expressed proteins in the heart, its precise role there has remained unknown. Also unclear is how cardiomyocytes are protected against apoptosis. Here, we report that failing human hearts express less fortilin than do non-failing hearts. We also found that mice lacking fortilin in the heart (fortilin) die by 9 weeks of age due to extensive cardiomyocyte apoptosis and severe HF, which suggests that fortilin sustains cardiomyocyte viability. The lack of fortilin is also associated with drastic upregulation of p53 target genes in the hearts. The heart-specific deletion of p53 in fortilin mice extends their life spans from 9 to 18 weeks by mitigating cardiomyocyte apoptosis. Our data suggest that fortilin is a novel cardiac p53 inhibitor and that its inadequate expression in failing hearts and subsequent overactivation of the p53 apoptosis pathway in cardiomyocytes exacerbates HF.
心力衰竭（HF）在发达国家已呈流行态势，全球有超过2000万人受其影响。尽管有现代医学和器械治疗手段，但60%-70%的HF患者在确诊后5年内仍会死亡，因为它会通过心肌细胞普遍的凋亡性损失而无情地进展。尽管福替林是一种含172个氨基酸的抗p53分子，是心脏中表达最多的蛋白质之一，但其在心脏中的精确作用仍不清楚。同样不清楚的是心肌细胞如何受到保护以免于凋亡。在此，我们报告，衰竭的人类心脏中福替林的表达低于非衰竭心脏。我们还发现，心脏中缺乏福替林（fortilin）的小鼠在9周龄时死亡，原因是广泛的心肌细胞凋亡和严重的HF，这表明福替林维持心肌细胞的活力。福替林的缺乏还与心脏中p53靶基因的急剧上调有关。在福替林基因敲除小鼠中特异性敲除心脏中的p53，可通过减轻心肌细胞凋亡将其寿命从9周延长至18周。我们的数据表明，福替林是一种新型的心脏p53抑制剂，其在衰竭心脏中的表达不足以及随后心肌细胞中p53凋亡途径的过度激活会加剧HF。
