Abstract 5942: Mechanotransduction-related Signalling Via Focal Adhesion Kinase Is Preserved In Pressure Overload Hypertrophy But Absent In Congestive Cardiomyopathy Despite Upregulated Melusin And β1-integrin
Background. Melusin is a muscle specific protein that binds to β1-integrin. This complex mediates mechanotransduction-dependent hypertrophic signalling via focal adhesion kinase (FAK). Deletion of melusin is associated with development of heart failure in experimental pressure overload hypertrophy (POH).
Aim. To investigate whether β1-integrin, melusin and FAK are altered in human cardiac POH and failure.
Methods. LV biopsies were obtained in 8 patients (pts) with normal LV function (C) undergoing cardiac bypass surgery, in 17 pts with aortic stenosis (AS) undergoing aortic valve replacement and in 15 pts with congestive cardiomyopathy (CCMP) at cardiac catheterization. LV message levels of adult β1 integrin isoform (ITGB1D), FAK and melusin were determined by real time quantitative TaqMan PCR (relative units). Protein levels were determined by Western Blotting including FAK phosphorylation analysis.
Results. (Table⇓) LV ejection fraction (EF) was lower in CCMP vs C and AS. LV mass index was increased in AS and CMP pts. In contrast, relative wall thickness (RWT, 2x posterior wall thickness/LV diastolic diameter) was increased in AS pts vs C and was lower in CCMP pts vs AS pts. ITGB1D and melusin message levels were significantly increased in pts with dilated cardiomyopathy vs C. In AS pts, ITGB1D expression tended to be higher but melusin expression remained unchanged vs C. Transcriptional changes were corroborated by the Western blotting (not shown). Note, though FAK gene and protein expression were similar in AS and CCMP pts vs C, phosphorylation of FAK at Tyr-397 was detected only in AS pts.
Conclusion. β1D-integrin and melusin are elevated in pts with CCMP. Nevertheless, FAK phosphorylation was preserved only in pressure overload hypertrophy. Absence of FAK phosphorylation despite increased melusin and β1-integrin levels suggests intracellular disruption of the mechanotransduction-dependent hypertrophic signalling in the failing myocardium.