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Heart failure is a complex syndrome that results from acute injury, such as myocardial infarction or from more long-standing diseases such as pressure and volume overload. The pathophysiological substrate of heart failure during the overall process of heart tissue remodeling includes not only cardiomyocytes but also interstitial tissue, fibroblasts, inflammatory cells, and endothelial cells. More recently, several lines of evidence have involved T lymphocytes in cardiac remodeling. OX40, which belongs to the TNF-receptor family, is a costimulatory receptor that can potentiate T cell receptor signaling on the surface of T lymphocytes. The role of OX40 in non-immune systems, particularly the cardiovascular system, has not been defined. In this study, we explore the role of OX40 in pressure overload induced cardiac remodeling.
Aortic banding (AB) was performed to induce cardiac hypertrophy in male OX40 global knockout mice and their wild-type littermates. 8 weeks after AB, cardiac function of mice was examined by echocardiography and hemodynamics. The extent of cardiac hypertrophy was also evaluated by pathological and molecular analyses of heart samples. The inflammatory response was evaluated after 2 weeks of AB by real-time quantitative RT-PCR and immunofluorescence staining.
The function of CD4 T lymphocytes from WT mice and OX40 knockout mice spleen were detected by cell counting Kit 8 and ELISA. Neonatal rat cardiomyocytes (NRCMs) co-cultured with the activated supernatant of CD4 T lymphocyte from each group were stimulated with Ang II. The extent of cardiomyocyte hypertrophy was determined by immunofluorescence staining and Western Blotting.
A noticeable increase in OX40 expression during cardiac remodeling in rodent heart was observed, while the expression of OX40 in cardiomyocytes was extremely low both under baseline and after stimulation. OX40-KO mice exhibited significantly ameliorated cardiac hypertrophy and fibrosis, inflammation and preserved cardiac function compared with wild-type mice after 8 weeks of aortic banding.
Furthermore, CD4 T lymphocyte proliferation and pro-inflammatory cytokine release were significantly diminished, while anti-inflammatory cytokine release was extremely enlarged in OX40 KO mice compared with wild-type mice as assessed by CCK-8 assay and ELISA. Co-culturing NRCMs with the activated supernatant of CD4 T lymphocytes from OX40 KO mice reduced the hypertrophy response in cardiomyocytes.
OX40 deficiency ameliorates pressure overload-induced cardiac hypertrophy, fibrosis, dysfunction, and inflammation. OX40 alters the pathology of cardiac remodeling via the modulation of CD4 T cell function.