PYK2 expression and phosphorylation increases in pressure overload-induced left ventricular hypertrophy

Abstract

Proline-rich tyrosine kinase 2 (PYK2) is a member of the focal adhesion kinase (FAK) family of nonreceptor protein tyrosine kinases. PYK2 has been implicated in linking G protein-coupled receptors to activation of mitogen-activated protein kinase cascades and cellular growth in a variety of cell types. To determine whether PYK2 expression and phosphorylation is altered in left ventricular (LV) myocardium undergoing LV hypertrophy (LVH) and heart failure in vivo, suprarenal abdominal aortic coarctation was performed in 160-g male Sprague-Dawley rats. Immunohistochemistry and Western blotting were performed on LV tissue 1, 8, and 24 wk after aortic banding. Aortic banding produced sustained hypertension and gradually developing LVH. PYK2 levels were increased 1.8 Ϯ 0.2-, 2.7 Ϯ 0.6-, and 2.0 Ϯ 0.2-fold in 1-, 8-, and 24-wk banded animals compared with their respective sham-operated controls. The increase in PYK2 expression was paralleled by an increase in PYK2 phosphorylation, both of which preceded the development of LVH. Immunohistochemistry revealed that enhanced PYK2 expression occurred predominantly in the cardiomyocyte population. Furthermore, there was a high degree of correlation (R ϭ 0.75; P Ͻ 0.001) between the level of PYK2 and the degree of LVH in 24-wk sham and banded animals. In contrast, FAK levels and FAK phosphorylation were not increased before the development of LVH. However, there was a high degree of correlation (R ϭ 0.68; P Ͻ 0.001) between the level of FAK and the degree of LVH in 24-wk sham and banded rats. There was also a significant increase in the ratio of phosphospecific anti-FAK to FAK at this time point. These data are consistent with a role for PYK2 in the induction of pressure overload-induced cardiomyocyte hypertrophy, and suggest that PYK2 and FAK have distinctly different roles in LVH progression. signal transduction; cytoskeleton; heart failure; focal adhesion kinase CARDIAC HYPERTROPHY is a compensatory process that leads to a heart better suited for the functional demands caused by myocyte dysfunction or loss. Because cardiac myocytes are terminally differentiated and nonproliferative, hypertrophic myocytes demonstrate an increase in protein content rather than an increase in myocyte number. Cardiac hypertrophy is also associated with sarcomeric reorganization and characteristic changes in gene expression and protein turnover. Cardiac hypertrophy, however, may independently lead to cardiac dysfunction and is also a common feature associated with the heart failure state. Despite advancements in the treatment and understanding of the pathogenesis of heart failure, the cellular and molecular mechanisms involved in hypertrophy induction are still largely unknown.Recent studies (12,17,18) have suggested that nonreceptor protein tyrosine kinases are important in transducing mechanical stimuli to biochemical pathways that lead to cardiomyocyte hypertrophy. Prolinerich tyrosine kinase 2 (PYK2) and focal adhesion kinase (FAK) are members of the FAK family of nonreceptor protein tyrosin...

Cardiomyocyte Apoptosis Triggered by RAFTK/pyk2 via Src Kinase Is Antagonized by Paxillin

“…RAFTK/pyk2 concentration in cardiomyocytes is much greater in neonates than adults and is highly dependent on calcium transients and contractility (26). Consistent with our findings in the pathologically altered myocardium (7), increased expression and phosphorylation of RAFTK/pyk2 were noted following left ventricular hypertrophy induced by pressure overload (28). We found overexpression of WT RAFTK/pyk2 caused dramatic changes in myofibril organization consistent with a role in reorganization of focal adhesions and cytoskeleton and demonstrated that RAFTK/pyk2 is activated in dilated cardiomyopathy (7).…”

CRNK gene transfer improves function and reverses the myosin heavy chain isoenzyme switch during post-myocardial infarction left ventricular remodeling

“…The Ca 2+ -dependent, nonreceptor protein tyrosine kinase PYK2 has been previously implicated in cardiomyocyte cell signaling pathways leading to LVH and HF (2)(3)(4)(5)(6). PYK2 is a member of the focal adhesion kinase (FAK) family of nonreceptor PTKs.…”

RhoA/ROCK signaling is critical to FAK activation by cyclic stretch in cardiac myocytes

“…Recent developments in this field indicate that the integrity of structures such as the Z disk, costamere, and intercalated disk is critically important to the ability of cardiac cells to appropriately respond to mechanical stress (4,11,21,32,37,41). It has been hypothesized that such structures participate in monitoring of mechanical force and in communication of strain to signaling molecules in cardiac myocytes (12,29,37).Focal adhesion kinase (FAK), a tyrosine kinase linked to integrin signaling (15,24,42), has been shown to be rapidly activated by mechanical stimuli in cardiac myocytes (2,5,9,12,13,23,34,39). Several lines of evidence support a role for FAK in the regulation of early gene transcription in response to hypertrophic agonists and mechanical stress (10,22,28,38,39), indicating that this kinase may coordinate the convergence of multiple signaling pathways involved in the hypertrophic growth of cardiac myocytes.…”

“…Focal adhesion kinase (FAK), a tyrosine kinase linked to integrin signaling (15,24,42), has been shown to be rapidly activated by mechanical stimuli in cardiac myocytes (2,5,9,12,13,23,34,39). Several lines of evidence support a role for FAK in the regulation of early gene transcription in response to hypertrophic agonists and mechanical stress (10,22,28,38,39), indicating that this kinase may coordinate the convergence of multiple signaling pathways involved in the hypertrophic growth of cardiac myocytes.…”