AIM: @entity296 ( @entity296 ), an early and frequent event of @entity1850 ( @entity1850 ), is characterized by reduced contractility irrespective of enhanced adrenergic stimulation. Phosphoinositide-3 kinase y (PI3Ky) is known to prevent b-adrenergic overstimulation via its scaffold function by activating major cardiac phosphodiesterases and restricting @entity268 levels. However, the role of PI3Ky in @entity1850 -induced @entity296 is unknown. This study is aimed at determining the specific role of lipid kinase-dependent and -independent functions of PI3Ky in the pathogenesis of @entity1850 -induced @entity296 . METHODS AND RESULTS: PI3Ky knockout @entity19 (PI3Ky(-/-)), @entity19 expressing catalytically inactive PI3Ky (PI3Ky( @entity573 / @entity573 )) and wild type @entity19 (P3Ky(+/+)) were exposed to lipopolysaccharide (LPS)-induced systemic @entity32 and assessed for survival, cardiac autonomic nervous system (ANS) function and left ventricular performance. Additionally, primary adult cardiomyocytes were used to analyze PI3Ky effects on myocardial contractility and inflammatory response. @entity1850 -induced adrenergic overstimulation induced a transient hypercontractility state in PI3Ky(-/-) @entity19 followed by reduced contractility. In contrast, P3Ky(+/+) @entity19 and PI3Ky( @entity573 / @entity573 ) @entity19 developed an early and ongoing @entity296 despite exposure to similarly increased @entity5733 levels. Compared to cells from P3Ky(+/+) and PI3Ky( @entity573 / @entity573 ) @entity19 cardiomyocytes from PI3Ky(-/-) @entity19 showed an enhanced and prolonged @entity268 -mediated signaling upon @entity1063 and an intensified LPS-induced proinflammatory response characterized by NFAT-mediated @entity13633 upregulation. CONCLUSIONS: This study reveals the lipid kinase-independent scaffold function of PI3Ky as a mediator of @entity296 during @entity32 -induced @entity1850 . Activation of cardiac phosphodiesterases via PI3Ky is shown to restrict @entity296 early after @entity1850 induction as well as the subsequent inflammatory responses.

Phosphoinositide 3-kinase gamma controls @entity32 -induced @entity296 via sequential @entity268 - and XXXX - signaling.

@entity268 :: ('CHEBI:17489', 'Chemical') :: ['cAMP'] @entity32 :: ('MESH:D007249', 'Disease') :: ['inflammation'] @entity296 :: ('MESH:D009202', 'Disease') :: ['myocardial hypercontractility', 'SIMD', 'myocardial depression', 'Sepsis-induced myocardial depression'] @entity573 :: ('MESH:C537014', 'Disease') :: ['KD'] @entity5733 :: ('D002395', 'Chemical') :: ['catecholamine'] @entity19 :: ('10090', 'Species') :: ['mice'] @entity13633 :: ('18126(Tax:10090)', 'Gene') :: ['iNOS'] @entity1850 :: ('MESH:D018746', 'Disease') :: ['SIRS', 'infection-induced systemic inflammatory response syndrome'] @entity1063 :: ('MESH:D009638', 'Chemical') :: ['norepinephrine']
@entity13633 :: (18126(Tax:10090),Gene) :: ['iNOS']
