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Breaking the Heat Tolerance Response: The Crucial Role of MFAP4 in Combating Heat‐Induced Cardiac Injury

Year: 2026

Type: article

Abstract: Heat exposure increases cardiac workload and impairs thermoregulation, leading to cardiac injury and heatstroke (HS). The involvement of Microfibrillar-associated protein 4 (MFAP4) in HS remains unclear. This study aims to investigate the role and mechanisms of MFAP4 in heat-induced damage. Whole body MFAP4-knockout (MFAP4-KO) mice and MFAP4-overexpressing cells were generated. Physiological and pathological responses were assessed in vivo/vitro experiments. An HS model exposed mice to (39.5 ± 0.5)°C/(55 ± 5)% humidity; and cell to 44°C with 5% CO₂ for 2 h. Transcriptomic analysis was performed to investigate the mechanisms underlying myocardial injury. MFAP4-KO mice exhibited accelerated core temperature rise, recovery of core temperature to 36.5°C was delayed, and reduced survival during HS (p < 0.05). HS induced left ventricular dilation (elevated LVIDd/LVIDs), systolic dysfunction (reduced EF/FS), myocardial injury (increased serum cTnT/cTnI), and fibrosis, all of which were exacerbated by MFAP4 deficiency. HS significantly elevated MFAP4 levels in serum and aorta, while MFAP4 deficiency mice hearts showed compensatory activation of the HSF1/HSP70 signaling pathway. MFAP4 overexpression increased cellular resistance to HS. Transcriptomic analysis revealed a 79% reduction in heat-responsive genes, and reversed 98 genes, confirming MFAP4 as a central cardiac protective role regulator of HS. MFAP4 deficiency also influenced Zbp1, Ccl12, and Cxcl10 expression through thermogenesis, and vascular smooth muscle contraction pathways. MFAP4 is a critical mediator of cardiovascular protection during acute HS. Its deficiency leads to thermoregulatory failure, and disrupts myocardial proteostasis by impairing the HSF1/HSP70 signaling axis, thereby exacerbating cardiac injury. MFAP4 likely increases myocardial resilience by regulating a ZBP1/CXCL10-centered network, thereby exerting a cardioprotective effect.

Source: The FASEB Journal

DOI: 10.1096/fj.202503662rr