Accession Number : ADA533881


Title :   Hepatocyte Growth Factor Inhibits Apoptosis by the Profibrotic Factor Angiotensin II via Extracellular Signal-regulated Kinase 1/2 in Endothelial Cells and Tissue Explants


Descriptive Note : Journal article


Corporate Author : UNIFORMED SERVICES UNIV OF THE HEALTH SCIENCES BETHESDA MD DEPT OF PHARMACOLOGY


Personal Author(s) : Lee, Young H ; Marquez, Ana P ; Mungunsukh, Ognoon ; Day, Regina M


Full Text : https://apps.dtic.mil/dtic/tr/fulltext/u2/a533881.pdf


Report Date : 01 Dec 2010


Pagination or Media Count : 12


Abstract : Hepatocyte growth factor (HGF), an endogenous tissue repair factor, attenuates apoptosis in many primary cell types, but the mechanism is not completely understood. Our laboratory demonstrated that angiotensin (Ang) II activates the intrinsic apoptotic pathway in primary endothelial cells (ECs) via reduction of the antiapoptotic protein Bcl-xL. Ang II decreased Bcl-xL mRNA half-life by reducing its binding to nucleolin, a protein that normally binds a 3 AU-rich region and stabilizes Bcl-xL mRNA. We hypothesized HGF may block apoptosis induced by Ang II. We used primary EC and ex vivo cultures of rat lung tissue to investigate HGF inhibition of Ang II-induced apoptosis. Our data indicated HGF abrogated Ang II-induced apoptosis by inhibiting cytochrome c release, caspase-3 activation, and DNA fragmentation. RNA-immunoprecipitation experiments demonstrated that HGF stabilized Bcl-xL mRNA by increasing nucleolin binding to the 3-untranslated region that was associated with cytoplasmic localization of nucleolin. Cytoplasmic localization of nucleolin and Bcl-xL mRNA stabilization required HGF activation of extracellular signal-regulated kinase (ERK)1/2, but not phosphatidylinositol 3-kinase. HGF also blocked Ang II-induced caspase-3 activation and lactate dehydrogenase release in tissue explants in an ERK-dependent manner.


Descriptors :   *CELLS(BIOLOGY) , *ANGIOTENSIN , *APOPTOSIS , MOLECULAR BIOLOGY , INHIBITION , LACTIC DEHYDROGENASE , ENDOTHELIUM , TISSUES(BIOLOGY) , PHOSPHORUS TRANSFERASES , DEOXYRIBONUCLEIC ACIDS , FRAGMENTATION , GROWTH SUBSTANCES


Subject Categories : Genetic Engineering and Molecular Biology
      Anatomy and Physiology
      Pharmacology


Distribution Statement : APPROVED FOR PUBLIC RELEASE