Uncoupling between enhanced excitation–contraction coupling and the response to heart disease: Lessons from the PI3Kγ knockout murine model

Loss of p47 phox Subunit Enhances Susceptibility to Biomechanical Stress and Heart Failure Because of Dysregulation of Cortactin and Actin Filaments

“…[13][14][15] Mechanotransduction involves the interaction between cytoskeletal proteins with extracellular matrix and cell adhesion complexes (cell-cell), leading to the intercellular transmission of mechanical force propagated via these 2 distinct yet interdependent mechanisms by directly stretching and straining neighboring cells. [13][14][15] N-cadherin, an intercalated disk protein located at adherens junction, mediates cell-cell mechanotransduction because of its mechanosensory property. 13,16,17,39,53 N-cadherin through β-catenin and α-catenin attaches to cytoskeletal F-actin, which creates the basis of cell adhesion and mechanosensory element.…”

“…[13][14][15] N-cadherin, an intercalated disk protein located at adherens junction, mediates cell-cell mechanotransduction because of its mechanosensory property. 13,16,17,39,53 N-cadherin through β-catenin and α-catenin attaches to cytoskeletal F-actin, which creates the basis of cell adhesion and mechanosensory element. Biomechanical stress at intercellular junction, sensed by N-cadherin, promotes actin polymerization through phosphatidylinositol-4,5 bisphosphate-mediated regulation of gelsolin and actin assembly.…”

“…13,17,46 Immunofluorescence staining and Western blot analyses on the membrane fraction exhibited minimal alterations in N-cadherin ( Figure 4E and 4F) and β-catenin ( Figure 4G and 4H) protein levels in WT hearts at baseline and after TAC at 5 weeks, whereas these proteins were markedly upregulated at intercalated disks in p47 phox KO LV after pressure overload. Defective phosphorylation of FAK and cortactin and the reduced association of Arp2/3 with cortactin indicate a possible defect in the intracellular cytoskeletal network in p47 phox KO-TAC hearts.…”

“…[13][14][15] N-cadherinmediated cell adhesion and the stretch sensor machinery in cardiomyocytes play key roles in the complex mechanism leading to cardiac myocyte remodeling. 13,16,17 Although the association of cortactin with N-cadherin and subsequent phosphorylation of cortactin are prerequisites for intercellular adhesion forces strengthening and cytoskeletal remodeling via actin polymerization, 18,19 the mechanisms controlling these interactions are poorly understood. Using the transverse aortic constriction (TAC) model, we showed that loss of p47 phox leads to enhanced susceptibility to pressure overload-induced biomechanical stress, leading to early heart failure and free wall rupture.…”

“…13,16,39 Activation of several signaling pathways such as Src kinase, focal adhesion kinase (FAK), Akt, and extracellular signal-regulated kinase 1/2 are key mediators of the response to biomechanical stress. [40][41][42][43] c-Src is present exclusively in the cytoskeletal fraction of pressure-overloaded myocardium 43 and phosphorylates various proteins, including cortactin and FAK.…”