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Focal Adhesion Signaling Down‐Regulation Increases Myocyte Apoptosis During Acute Stress of Volume Overload: Role of Beta1‐Adrenergic Receptor Stimulation
Author(s) -
seqqat rachid,
Rafiq Khadija,
Hanscom Marie,
Margulies Kenneth,
Houser Steven,
Dell'Italia Louis,
Sabri Abdelkarim
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.879.2
Subject(s) - myocyte , pten , cardiac myocyte , signal transduction , apoptosis , medicine , endocrinology , microbiology and biotechnology , tensin , focal adhesion , phosphorylation , chemistry , biology , pi3k/akt/mtor pathway , biochemistry
We examined the role of ß1‐adrenergic receptors (ß1‐ARs) in focal adhesion (FA) signaling alteration and myocyte apoptosis in acute stress of volume overload (VO). Rats subjected to aorto‐caval fistula (ACF) developed cardiac dilatation associated with a decrease in interstitial collagen deposition along with a decrease in tyrosine phosphorylation of key FA signaling molecules FAK, Pyk2, and paxillin. This impared FA signaling induced by ACF was associated with an increase in myocyte apoptosis. ß1‐AR blockade (extended‐release metoprolol succinate, 100 mg QD) prevented collagen loss, FA signaling down‐regulation, and myocyte apoptosis induced by ACF at 2 days, but failed to reduce cardiac dilatation and wall stress. The phosphatase PTEN activation was increased in ACF animals and this increase was prevented with ß1‐AR blockade. Chronic stimulation of cultured neonatal rat cardiomyocytes with ß1‐AR agonist or expression of ß1‐ARs induced PTEN activation, FA signaling down‐regulation, and myocyte apoptosis. Moreover, expression of a catalytically inactive PTEN mutant or wild‐type FAK prevented ß1‐AR‐induced myocyte apoptosis. These results show that PTEN activation and FA signaling alteration are critical downstream signals for myocyte apoptosis following ß1‐AR stimulation in‐vitro and affects myocyte‐extracellular matrix scaffolding necessary for cardiac remodeling during acute VO.