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Updated: Sep 23, 2025
Generation and Expansion of Human Cardiomyocytes from Patient Peripheral Blood Mononuclear Cells
Published on: February 12, 2021
CXCL10 is a novel anti-angiogenic factor downstream of p53 in cardiomyocytes
Tri Wahyuni1,2, Shota Tanaka1, Ryuta Igarashi1
1Laboratory of Clinical Science and Biomedicine, Graduate School of Pharmaceutical Sciences, Osaka University, Suita City, Osaka, Japan.
Abstract:
Tumor suppressor protein p53 plays crucial roles in the onset of heart failure. p53 activation results in cardiac dysfunction, at least partially by suppressing angiogenesis. Though p53 has been reported to reduce VEGF production by inhibiting hypoxia-inducible factor, the anti-angiogenic property of p53 remains to be fully elucidated in cardiomyocytes. To explore the molecular signals downstream of p53 that regulate vascular function, especially under normoxic conditions, DNA microarray was performed using p53-overexpressing rat neonatal cardiomyocytes. Among genes induced by more than 2-fold, we focused on CXCL10, an anti-angiogenic chemokine. Real-time PCR revealed that p53 upregulated the CXCL10 expression as well as p21, a well-known downstream target of p53. Since p53 is known to be activated by doxorubicin (Doxo), we examined the effects of Doxo on the expression of CXCL10 and found that Doxo enhanced the CXCL10 expression, accompanied by p53 induction. Importantly, Doxo-induced CXCL10 was abrogated by siRNA knockdown of p53, indicating that p53 activation is necessary for Doxo-induced CXCL10. Next, we examined the effect of hypoxic condition on p53-mediated induction of CXCL10. Interestingly, CXCL10 was induced by hypoxia and its induction was potentiated by the overexpression of p53. Finally, the conditioned media from cultured cardiomyocytes expressing p53 decreased the tube formation of endothelial cells compared with control, analyzed by angiogenesis assay. However, the inhibition of CXCR3, the receptor of CXCL10, restored the tube formation. These data indicate that CXCL10 is a novel anti-angiogenic factor downstream of p53 in cardiomyocytes and could contribute to the suppression of vascular function by p53.
Insights
Tumor suppressor protein p53 activates CXCL10 in cardiomyocytes, inhibiting blood vessel formation. This finding reveals a new mechanism for p53
Area of Science:
- Cardiovascular Biology
- Molecular Biology
- Oncology
Background:
- The tumor suppressor protein p53 is implicated in heart failure development.
- p53 activation can lead to cardiac dysfunction, partly by inhibiting angiogenesis.
- The precise anti-angiogenic mechanisms of p53 in cardiomyocytes require further elucidation.
Purpose of the Study:
- To identify downstream molecular signals of p53 that regulate vascular function in cardiomyocytes, particularly under normoxic conditions.
- To investigate the role of the chemokine CXCL10 as a potential mediator of p53's anti-angiogenic effects.
Main Methods:
- DNA microarray analysis of p53-overexpressing rat neonatal cardiomyocytes.
- Real-time PCR to validate gene expression (CXCL10, p21).
- Doxorubicin treatment to induce p53 and assess CXCL10 expression.
- siRNA knockdown of p53 to confirm its role in CXCL10 induction.
- Hypoxia exposure to study p53-mediated CXCL10 induction.
- In vitro angiogenesis assay using endothelial cells and conditioned media from cardiomyocytes.
- Inhibition of CXCR3 to assess the role of the CXCL10 receptor.
Main Results:
- p53 overexpression upregulated the expression of CXCL10 and p21 in cardiomyocytes.
- Doxorubicin treatment induced p53 and enhanced CXCL10 expression, an effect dependent on p53.
- Hypoxia also induced CXCL10, with its induction further potentiated by p53 overexpression.
- Conditioned media from p53-expressing cardiomyocytes inhibited endothelial cell tube formation.
- Inhibition of CXCR3 reversed the anti-angiogenic effect, confirming CXCL10's role.
Conclusions:
- CXCL10 is identified as a novel downstream anti-angiogenic factor regulated by p53 in cardiomyocytes.
- p53-induced CXCL10 contributes to the suppression of vascular function in the heart.
- This study provides new insights into the molecular mechanisms linking p53, cardiac dysfunction, and impaired angiogenesis.
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