【Background】
p53 is reported to play important roles in the onset and progression of heart failure (HF) after myocardial injury. However, it remains to be fully elucidated how p53 works in cardiomyocytes.
【Methods & Results】
Neonatal rat cardiomyocytes were infected with adenoviral vectors expressing p53 and cultured for 48hr. DNA microarray analysis revealed that p53 overexpression resulted in the increased expression of inflammation-related genes, including CXCL10, an anti-angiogenic factor. RT-qPCR experiments showed that the expression of CXCL10 was upregulated by p53, while that of VEGF was not influenced. Next, we examined whether CXCL10 increased in HF animal models. In myocardial infarction (MI) model, the expression of CXCL10 was upregulated after MI both at acute and chronic stages, accompanied by the induction of p53. Moreover, in experimental autoimmune myocarditis models, CXCL10 expression was upregulated at chronic phase in myocardium specific STAT3 knockout mice which exhibited severe HF. Consistent with the previous studies, CXCL10 suppressed the migration of endothelial cells. Finally, since p53 is reported to exhibit anti-angiogenic property by interacting with HIF-1, we examined the effects of hypoxia on CXCL10 expression and found that hypoxia synergistically elevated the mRNA expression of CXCL10 with p53.
【Conclusion】
CXCL10, anti-angiogenic chemokine, is induced by p53, and this effect is enhanced by hypoxia pathways. Considering that impaired angiogenesis causes HF, CXCL10 could be a novel therapeutic target of HF.