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Absence of Gravin Scaffolding to the β 2 ‐AR Protects against Heart Failure and its Protective Effects are Additive to Carvedilol Treatment Alone
Author(s) -
Singh Sonal,
Suryavanshi Santosh,
Diaz Diaz Andrea,
McConnell Bradley
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.1025.3
Subject(s) - contractility , carvedilol , heart failure , muscle hypertrophy , chemistry , stimulation , medicine , receptor , endocrinology , pharmacology
Gravin, an A‐Kinase Anchoring Protein (AKAP) is a scaffolding protein in the heart involved in the modulation of cardiac contractility. Specifically, gravin scaffolds PKA, PKC, β‐arrestin and various other proteins to β 2 ‐adrenergic receptors (β 2 ‐ARs) and functions to modulate contractility by mediating β 2 ‐ARs desensitization. We previously found that disruption of gravin scaffolding, using gravin knockout (gravin‐t/t) mice, reduced cardiac hypertrophy induced by chronic β‐AR stimulation with isoproterenol (ISO; 60mg/kg/day for 14 days). However, for disruption of gravin scaffolding to be considered a therapeutic target, it will be important to show that inhibiting gravin scaffolding is a superior approach over conventional therapies. Hence, the goal of this study was to study the effects of carvedilol (CARV) in wild‐type (WT) versus gravin‐t/t animals; where CARV is the gold standard β‐blocker used to treat human heart failure (HF). WT and gravin‐t/t mice were treated with ISO chronically for 2‐weeks to induce heart failure and then treated with CARV for additional 3‐weeks. We found that heart‐to‐body weight (HW/BW) ratio, an indicator of cardiac hypertrophy, was significantly lower in the gravin‐t/t‐ISO versus WT‐ISO mice. Following CARV treatment, HW/BW was further decreased in the gravin‐t/t‐CARV mice. In addition, hemodynamic pressure‐volume measurements of contractility (dp/dt max , Ees, cardiac output) and relaxation (Tau) were significantly greater in gravin‐t/t CARV mice as compared to WT‐CARV mice. Our data suggests that the absence of gravin scaffolding in gravin‐t/t mice has a protective role in HF, exceeding the positive effects of CARV alone.