DataSheet1_Unveiling the proteome of the fasting heart: Insights into HIF-1 pathway regulation.PDF

Fasting is a common dietary intervention known for its protective effects against metabolic and cardiovascular diseases. While its effects are mostly systemic, understanding tissue-specific changes in the heart is crucial for the identification of the mechanisms underlying fasting-induced cardioprotection. In this study, we performed a proteomic analysis of the fasting heart and attempted to clarify the molecular basis of fasting-induced cardioprotection. Our investigation identified a total of 4,652 proteins, with 127 exhibiting downregulation and 118 showing upregulation after fasting. Annotation analysis highlighted significant changes in processes such as lipid metabolism, the peroxisome pathway, and reactive oxygen species metabolism. Notably, the HIF-1 signaling pathway emerged as one of the focal points, with various HIF-1 targets exhibiting differential responses to fasting. Further experiments demonstrated downregulation of HIF-1α at both transcript and protein levels. Intriguingly, while gene expression of Egln3 decreased, its protein product PHD3 remained unaffected by fasting. The unchanged levels of pro-inflammatory cytokines indicated that the observed reduction in Hif1a expression did not stem from a decrease in basal inflammation. These findings underscore the complex regulation of the well-established cardioprotective HIF-1 signaling within the heart during 3-day fasting.

禁食是一种常见的膳食干预手段，因其对代谢性疾病与心血管疾病具有保护作用而广受认可。尽管禁食的生物学作用多呈全身性，但若要明确禁食诱导心脏保护作用的潜在分子机制，解析心脏组织的特异性变化至关重要。本研究对禁食状态下的心脏开展蛋白质组学分析，旨在阐明禁食诱导心脏保护作用的分子基础。本次研究共鉴定到4652种蛋白质，其中127种在禁食后表达下调，118种表达上调。注释分析结果显示，脂质代谢、过氧化物酶体通路以及活性氧代谢等多个生物学过程发生了显著变化。值得注意的是，缺氧诱导因子-1（HIF-1）信号通路成为核心调控通路之一，多种HIF-1靶基因对禁食呈现出差异化响应。后续实验证实，HIF-1α在转录与蛋白水平均出现下调。有趣的是，尽管Egln3的基因表达水平有所下降，但其编码的蛋白产物脯氨酰羟化酶3（PHD3）并未受禁食影响。促炎细胞因子水平未发生变化，这表明本次观测到的Hif1a表达下调并非源于基础炎症水平的降低。本研究结果证实，在3天禁食期间，心脏内公认的心脏保护性HIF-1信号通路存在复杂的调控机制。