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Systemic administration of CD28-deprived in vitro-induced regulatory T cell attenuates pathological remodeling caused by pressure overload-induced cardiac fibrosis

ABSTRACT: In heart failure, myocardial fibrosis driven by immune-mediated inflammation contributes to progressive cardiac dysfunction. We investigated the therapeutic efficacy of CD28-deprived in vitro–induced regulatory T cells (iTreg), a stable Treg subset, in a murine model of pressure overload–induced heart failure. CD28-deprived iTreg were intravenously administered one week after transverse aortic constriction (TAC). Treated mice showed improved cardiac function, reduced ventricular fibrosis, and Treg localization in the heart. Transcriptomic analysis revealed downregulation of profibrotic and proinflammatory pathways, including TNF-α/NF-κB and TGF-β signaling. These findings suggest that systemic delivery of CD28-deprived iTreg effectively modulates the inflammatory microenvironment and suppresses cardiac remodeling, offering a promising immunomodulatory strategy for treating heart failure.

ORGANISM(S): Mus musculus

PROVIDER: GSE300131 | GEO | 2026/03/11

REPOSITORIES: GEO

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Project description:To identify a novel target for the treatment of heart failure, we examined gene expression in the failing heart. Among the genes analyzed, 12/15 lipoxygenase (12/15-LOX) was markedly up-regulated in heart failure. To determine whether increased expression of 12/15-LOX causes heart failure, we established transgenic mice that overexpressed 12/15-LOX in cardiomyocytes. Echocardiography showed that 12/15-LOX transgenic mice developed systolic dysfunction. Cardiac fibrosis increased in 12/15-LOX transgenic mice with advancing age, and was associated with the infiltration of macrophages. Consistent with these observations, cardiac expression of monocyte chemoattractant protein-1 (Mcp-1) was up-regulated in 12/15-LOX transgenic mice compared with wild-type mice. Treatment with 12-hydroxy-eicosatetraenotic acid, a major metabolite of 12/15-LOX, increased MCP-1 expression in cardiac fibroblasts and endothelial cells, but not in cardiomyocytes. Inhibition of Mcp-1 reduced the infiltration of macrophages into the myocardium and prevented both systolic dysfunction and cardiac fibrosis in 12/15-LOX transgenic mice. Likewise, disruption of 12/15-LOX significantly reduced cardiac Mcp-1 expression and macrophage infiltration, thereby improving systolic dysfunction induced by chronic pressure overload. Our results suggest that cardiac 12/15-LOX is involved in the development of heart failure and that inhibition of 12/15-LOX could be a novel treatment for this condition. Heart failure is still one of the leading causes of death worldwide. Therefore, it is important to elucidate the underlying mechanisms of heart failure and develop more effective treatments for this condition. To clarify the molecular mechanisms of heart failure, we performed microarray analysis using cardiac tissue samples obtained from a hypertensive heart failure model (Dahl salt-sensitive rats). ~300 genes showed significant changes of expression in the failing hearts compared with control hearts. Among the genes analyzed, 12/15-lipoxygenase (12/15-LOX) was most markedly up-regulated in failing hearts compared with control hearts .

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Systemic administration of CD28-deprived in vitro-induced regulatory T cell attenuates pathological remodeling caused by pressure overload-induced cardiac fibrosis

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