Brain Behav Immun. 2026 Oct 18:107078. doi: 10.1016/j.bbi.2026.107078. Online ahead of print.
ABSTRACT
BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is commonly accompanied by sympathetic overactivation, contributing to poor patient prognosis. The paraventricular nucleus (PVN) and nucleus tractus solitarius (NTS) are critical cardiovascular regulatory centers. Pathological cardiolipin (CL) remodeling catalyzed by Acyl-CoA:lysocardiolipin acyltransferase 1 (ALCAT1) exacerbates disease progression. This study aims to elucidate the roles of aerobic exercise and ALCAT1 in modulating brain-heart axis dysregulation in HFpEF.
METHODS AND RESULTS: We employed wild-type (WT) and Alcat1 knockout mice to establish an HFpEF model, followed by aerobic exercise. Neuroinflammatory model was established to investigate the role of ALCAT1 in neuroinflammation. Underlying mechanisms were explored in HT22 cells. In HFpEF mice, aerobic exercise suppressed ALCAT1 and up-regulated growth differentiation factor 5 (GDF5) in the PVN and NTS, reduced pro-inflammatory cytokines, enhanced antioxidant enzyme activities, decreased oxidative stress markers, and attenuated neuronal structural damage and hyperactivation. These central improvements were accompanied by attenuated cardiac sympathetic overactivation, lowered blood pressure, and improved diastolic function. The important role of ALCAT1 was further supported, as its genetic knockout conferred significant protection in both HFpEF and neuroinflammatory models. In HT22 cells, GDF5 suppressed the LPS-induced ALCAT1 up-regulation and ameliorated cellular injury.
CONCLUSION: ALCAT1 is an important contributor to neuronal injury. Aerobic exercise suppresses ALCAT1 and up-regulates GDF5, ameliorating neuronal injury and improving diastolic function in HFpEF mice. Mechanistically, ALCAT1 and GDF5 are reciprocally regulated, which may contribute to the protective effects of aerobic exercise against HFpEF. These findings suggest ALCAT1 as a potential molecular target for exercise-based HFpEF therapy.
PMID:42893735 | DOI:10.1016/j.bbi.2026.107078