title: Uncoupling between enhanced excitation-contraction coupling and the response to heart disease: lessons from the PI3Kγ knockout murine model.
abstract: The heart is a mechanosensitive organ that adapts its morphology to changing hemodynamic conditions via a process named mechanotransduction, which is the primary means of detecting mechanical stress in the extracellular environment. In the heart, mechanical signals are propagated into the intracellular space primarily via cell adhesion complexes and are subsequently transmitted from cell to cell via paracrine signaling. Enhanced excitation-contraction coupling increases myocardial contractility in various experimental models. However, these animal models routinely show increased susceptibility to biomechanical stress with the development of early ventricular dilation and reduced systolic function in the setting of adverse myocardial remodeling. The enhanced susceptibility of the PI3Kγ knockout mice to biomechanical stress is linked to a cAMP-dependent up-regulation of matrix metalloproteinase with a loss of N-cadherin mediated cell adhesion. Enhancing cell-cell adhesion and cell-ECM interaction will promote the salutary effects of enhanced intracellular Ca(2+) cycling on whole heart function and booster the therapeutic potential of normalizing intracellular Ca(2+) cycling in patients with heart failure.
authors.affiliation: Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Canada. gavin.oudit@ualberta.ca
authors.forename: Danny
authors.initials: D
authors.lastname: Guo
authors.forename: Gayatri
authors.initials: G
authors.lastname: Thiyam
authors.forename: Sreedhar
authors.initials: S
authors.lastname: Bodiga
authors.forename: Zamaneh
authors.initials: Z
authors.lastname: Kassiri
authors.forename: Gavin Y
authors.initials: GY
authors.lastname: Oudit
mesh_terms: D000818:Animals; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000235:genetics*; D056966:Excitation Contraction Coupling / Q000235:genetics / Q000502:physiology*; D006331:Heart Diseases / Q000235:genetics* / Q000503:physiopathology*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological
chemical_list: D058544:Class Ib Phosphatidylinositol 3-Kinase; C546764:Pik3cg protein, mouse