Autoimmune diseases are characterized by persistent inflammatory responses mediated by cytokines such as IL-1β, IL-6, and TNF-α, which promote tissue remodeling. In cardiac tissue, these cytokines drive myeloid cell infiltration, endothelial adhesion, and damage, leading to tissue remodeling and fibrosis that can contribute to heart failure with preserved ejection fraction (HFpEF). HFpEF is a multifactorial syndrome marked by systemic inflammation, left ventricular diastolic dysfunction, and elevated levels of natriuretic peptides. Several studies have already demonstrated a positive correlation between high levels of IL-6 in patients serum and the probability of developing HFpEF. Using LysM-IL6OE mice, which overexpress IL-6 in myeloid cells, our study demonstrated that despite systemic inflammation, ejection fraction remained preserved in these animals. Western blot analysis revealed increased TGF-β1 levels in the heart, while qPCR showed upregulation of PAI-1, Col1a2, IL-1β, NOX2, and IFNγ. TGF-β1 was also upregulated in other organs associated with the cardiovascular system, including the kidney, liver, and aorta. Sirius Red staining showed increased collagen deposition, indicating cardiac fibrosis, and ELISA detected a mild increase in BNP levels in plasma. Echocardiographic analysis to assess diastolic dysfunction showed that LysM-IL6OE animals had a slight elevation in heart rate as well as increases in the E/A and E/E’ ratios. In parallel, thrombin generation assays indicated reduced platelet functionality, and flow cytometry revealed decreased expression of P-selectin and GPVI. These findings suggest that IL-6 overexpression in myeloid cells induces systemic inflammation and cardiovascular fibrosis, which may contribute to the development of HFpEF and platelet dysfunction.
