CCND1 Mitigates Ischemia-Induced Pathological Cardiac Remodeling by Promoting Cardiac Monocyte–Derived Macrophage Transition to a Reparative Phenotype

BACKGROUND: The innate immune system plays a pivotal role in orchestrating the response to myocardial infarction (MI), with monocytes and macrophages acting as central mediators of tissue injury and repair. Following MI, a dynamic sequence of inflammatory, anti-inflammatory, and reparative phases unfolds over the course of several days. While timely resolution of inflammation and initiation of reparative programs are critical for favorable cardiac remodeling and improved long-term outcomes, the mechanisms by which recruited monocyte-derived macrophages are instructed within the postinfarct niche to adopt a reparative phenotype remain incompletely understood. METHODS: Human peripheral blood mononuclear cells were isolated from individuals with and without MI for single-cell RNA sequencing analysis. The murine cardiac monocyte-derived macrophage behaviors after MI were characterized by genetic lineage tracing, lineage tracing plus bone marrow transplantation, metabolite profiling, and cell phenotyping approaches. The role of macrophage CCND1 (cyclin D1) in MI-induced adverse remodeling was investigated using macrophage-specific Ccnd1 knockout mice. Epigenetic experiments were conducted to study the mechanisms underlying metabolic reprogramming and macrophage phenotypic transition. The therapeutic efficacy of lentivirus-targeting macrophage CCND1 and its downstream regulator PDK4 (pyruvate dehydrogenase kinase 4) were assessed in vivo using an MI mouse model. RESULTS: We found that CCND1 levels in peripheral blood mononuclear cells, monocytes, and cardiac macrophages from patients with MI were significantly decreased. Both macrophage-specific and monocyte-derived macrophage–specific deletion of CCND1 worsened MI-induced cardiac dysfunction and adverse remodeling, driven by amplified inflammatory responses. Mechanistically, CCND1 directly interacted with PDK4 and facilitated its ubiquitination by recruiting RPL11 (ribosomal protein L11) and mouse double minute 2. Through this axis, CCND1 suppressed PDK4-driven PDH (pyruvate dehydrogenase) phosphorylation, enhanced glucose oxidation, and shifted macrophages toward an anti-inflammatory phenotype. Targeted overexpression of the CCND1-PDK4 binding motif or knockdown of PDK4 in macrophages improved cardiac function and mitigated adverse remodeling after MI, independent of the canonical cell cycle–regulatory role of CCND1. CONCLUSIONS: Our findings identify the CCND1-PDK4 axis as a key regulator of macrophage functional reprogramming toward a reparative phenotype after MI, highlighting it as a potential therapeutic target in postinfarction remodeling.