Targeting Senescent Macrophages to Improve Heart Failure Outcomes

/ABSTRACT Heart failure (HF) remains a leading cause of morbidity and mortality worldwide. Despite the availability of various therapies, preventing the maladaptive changes associated with HF continues to be a challenge. This R01 project will elucidate the mechanistic aspects of how cardiac tissue-resident macrophages (TRMs) contribute to adverse remodeling in the heart during HF. Our long-term goal is to target innate immune response in the heart to pause and even prevent HF progression. Over the past decade, the PI's lab and others have demonstrated that cardiac TRMs play cardioprotective roles in various cardiac diseases and HF conditions. However, preliminary studies on human failing hearts and mouse HF models showed that in HF conditions, cardiac TRMs transitioned into a pathologically senescent state (SenTRM), which correlates with cardiomyocyte (CM) stress and inflammation. Interestingly, this transition is reversible with interventions that can unload the failing heart, suggesting the therapeutic significance of SenTRM modulation in HF. The central hypothesis is that macrophage senescence promotes CM dysfunction in HF involving chronic inflammation and impaired clearance of CM debris, the mechanisms of which will be dissected in the following three aims. Aim 1 will determine whether TRM senescence contributes to CM inflammation through both the loss of steady-state TRMs and the rise of senescent TRMs. Aim 2 will determine whether SenTRMs have an impaired clearance function, specifically their role in removing CM mitochondrial debris—a key factor in heart function deterioration. Aim 3 will address the upstream mechanisms leading to TRM senescence, focusing on whether blocking Interleukin-6 signal reverses macrophage senescence. This project is conceptually and technically innovative, involving cutting-edge single-nucleus profiling, human patient-derived cell-based models, and mouse genetic tools to test the hypothesis and elucidate the underlying mechanisms of macrophage senescence in HF. The mechanistic insights gained from these studies will enable the development of novel therapeutic strategies that specifically target macrophage senescence to prevent adverse cardiac remodeling during HF. Thus, this project has a solid translational impact, opening new avenues for improving treatment outcomes in patients with HF, an area of high significance to NIH/NHLBI. Project Number: 1R01HL179012-01 | Fiscal Year: 2025 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: Xiao Li | Institution: TEXAS HEART INSTITUTE, HOUSTON, TX | Award Amount: $651,967 | Activity Code: R01 | Study Section: Integrative Myocardial Physiology/Pathophysiology A Study Section [MPPA] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01HL17901201