PhD (Doctor of Philosophy)
Date of Award
Committee Chair or Co-Chairs
David L. Williams, Krishna Singh, Tammy R. Ozment, Valentin P. Yakubenko
Heart failure after myocardial infarction (MI) remains the leading cause of mortality among all cardiovascular diseases globally. Angiogenesis plays a critical role in cardiac functional recovery after MI. Heat shock protein A12B (HSPA12B) is predominately expressed in endothelial cells and required for angiogenesis. Yes-associated protein (YAP) has been reported to promote tumor angiogenesis.
In the present study, we investigated the cooperative role of HSPA12B and YAP in angiogenesis following myocardial ischemic injury. Endothelial specific deficiency of HSPA12B (eHspa12b-/-) or YAP (eYap-/-) impairs angiogenesis and exacerbates cardiac dysfunction after MI, when compared with wild type (WT) mice. In addition, MI induced angiogenesis and the expression of angiogenic factors (angiopoietin-1, VEGF and VEGFR2) were impaired in both eHspa12b-/- and eYap-/- hearts. MI increased YAP expression and nuclear translocation in WT hearts, but not in eHspa12b-/- myocardium. Similarly, MI also markedly increased HSPA12B expression and nuclear translocation in WT mice but not in eYap-/- hearts.
In vitro data shows that overexpression of HSPA12B upregulated hypoxia induced endothelial cell proliferation, migration and angiogenesis. On the contrary, deactivation of YAP by verteporfin attenuates endothelial cell proliferation, migration and angiogenesis after hypoxic challenge. In accordance, silencing of either HSPA12B or YAP suppressed endothelial cell proliferation and angiogenesis promoted by hypoxia. Importantly, YAP inhibition abrogates HSPA12B induced endothelial cell proliferation and angiogenesis. Deficiency of HSPA12B suppresses YAP expression and nuclear translocation following hypoxia while knockdown of YAP attenuates hypoxia stimulated HSPA12B expression and nuclear translocation.
Mechanistically, hypoxia induced an interaction between endothelial HSPA12B and YAP. Of note, ChIP assay shows that HSPA12B is a target gene of YAP/transcriptional enhanced associated domain 4 (TEAD4). Further investigation indicates that HSPA12B also acts as a co-activator in YAP associated proliferation and angiogenesis. HSPA12B can stabilize YAP and prevent YAP from degradation.
Therefore, our results delineated a previously unrecognized role of endothelial HSPA12B as a novel target and co-activator for YAP/TEAD4 and cooperates with YAP to promote endothelial cell proliferation, migration and angiogenesis following myocardial ischemia.
Dissertation - unrestricted
Fan, Min, "Endothelial Heat Shock Protein A12B and Yes-associated Protein Cooperatively Promote Angiogenesis Following Myocardial Infarction" (2021). Electronic Theses and Dissertations. Paper 3944. https://dc.etsu.edu/etd/3944
Copyright by the authors.