Cytokine-induced Macrophage Transition Drives Cardiac Fibrosis and Diastolic Dysfunction

Heart disease remains the leading cause of death worldwide, with hypertension-induced cardiac dysfunction being a major precursor. A key pathological hallmark of this condition is cardiac fibrosis, characterized by excessive myocardial interstitial scar tissue that compromises ventricular elasticity and compliance. Despite its significance, effective therapies remain elusive due to an incomplete understanding of the mechanisms driving fibrosis. Emerging evidence highlights macrophages as active contributors to fibrotic remodeling via Macrophage-to-Myofibroblast Transition (MMT), previously observed in kidney fibrosis. However, the role of MMT in cardiac fibrosis remains unexplored. In this study, we investigate whether MMT contributes to hypertension-induced myocardial fibrosis and identify the molecular mechanisms involved, focusing on Interleukin-10 (IL-10) as a potential driver of this process. Using DOCA-salt hypertensive mice, a classic model of hypertension, we employed cutting-edge methodologies, including radiotelemetry, left ventricular catheterization, cardiac ultrasound, pressure-volume (PV) loop analysis, Seahorse metabolic analysis, and flow cytometry studies. Our findings revealed that DOCA-salt mice developed diastolic dysfunction by day 10, evidenced by impaired left ventricular relaxation (max -dp/dt), while ejection fraction and fractional shortening remained unaffected. Picrosirius red staining confirmed substantial cardiac fibrosis in hypertensive mice compared to sham controls. Flow cytometry analysis identified a significant increase in MMT cells (α-SMA + CD68 + ) within the hearts of DOCA-salt mice, suggesting a macrophage origin for myofibroblasts is a significant contributor to hypertensive-cardiac fibrosis. In vitro experiments demonstrated that IL-10 treatment of macrophages (RAW267.4 cells and primary bone-marrow-derived macrophages, BMDMs) markedly increased MMT populations. Furthermore, this effect was amplified under high-pressure conditions simulated using a specialized chamber, suggesting a synergistic interaction between elevated blood pressure and IL-10 in promoting fibrotic remodeling. Our findings establish MMT as a critical driver of hypertension-induced cardiac fibrosis and identify IL-10 as a pivotal modulator of macrophage phenotypic differentiation. Ongoing studies aim to validate these findings in vivo using genetically modified animals and to pinpoint the primary sources of IL-10 in the hypertensive heart. This study is the first to identify MMT in hypertensive hearts and to implicate IL-10 as a key driver of this process. These results uncover a novel mechanism of fibrotic remodeling in hypertension, positioning IL-10 as a promising therapeutic target for preventing fibrotic progression and reducing the risk of heart failure. NIH RO1-HL146713 NIH R25-GM083247 AHA 23TPA1076467 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.