Abstract 13122: Hax1 Mediates Hippo Pathway to Enhance Therapeutic Effect of Sca1+ Cardiac Stem Cell Against Myocardial Ischemia
Background: The Hippo pathway can regulate the fate and metabolic function of stem/progenitor cells through a kinase cascade that impinges on the transcription of growth-regulatory genes. This study investigates the role of HCLS-associated protein X-1 (HAX1) on the Hippo pathway with a goal of enhancing the therapeutic effects of sca1+ cardiac stem cells (CSCssca1+) in mouse ischemic hearts.
Methods and Results: Western Blot assessment showed that phosphorylation levels of Yes-associated protein (Yap), the terminal effector of Hippo pathway, was increased in CSCssca1+ when endogenous HAX1 gene expression was silenced, whereas lentiviral over-expression of HAX1 maintained Yap activation by inhibiting its phosphorylation at Serine-397. ImageStream flow cytometry was then used to observe the enhanced nuclear translocation of Yap. Hypoxia exposure promoted this translocation to a greater extent in HAX1-overexpressing CSCssca1+ (CSCsHAX1) than non-encoding DNA sequence-transduced CSCssca1+ (CSCsNull) (Fig 1A). HAX-1 over-expression enhanced cardioprotective molecular mechanisms by restraining the dissipation of mitochondrial membrane potential (Fig 1B), inhibiting endoplasmic reticulum stress response, promoting HIF-1α expression, and upregulating anti-fibrotic gene expression in CSCssca1+ response to hypoxia injury. Echocardiography and histological assessment demonstrated that contractile function was significantly improved and cardiac fibrosis was decreased in ischemic mouse hearts post engraftment of CSCsHAX1 when compared with those of the CSCsNull-transplanted group (Fig 1C).
Conclusion: HAX1 over-expression can regulate Hippo signal and promote nuclear translocation of Yap, upregulating intrinsic protective mechanisms of CSCssca1+. This results in greater improvement of cardiac function in ischemic hearts post transplantation of HAX1 over-expressing CSCssca1+.
Author Disclosures: W. Cai: None. L. Wang: None. W. Huang: None. C. Paul: None. M. Xu: None. R.W. Millard: None. Y. Wang: None.
- © 2015 by American Heart Association, Inc.