Disruption of Gravin's Scaffolding Protects against Isoproterenol Induced Heart Failure

Abstract

β‐adrenergic receptor (β‐AR) signaling is the primary mechanism to increase cardiac contractility. However, chronic β‐AR stimulation, which occurs in HF, results in impairment of the β‐adrenergic pathway, leading to reduced contractility due in part by desensitization of these receptors. To induce contractility, β‐ARs signal through protein kinase A (PKA)‐dependent phosphorylation, which affects calcium homeostasis. PKA binds to A‐kinase anchoring proteins (AKAPs), which localize PKA and its substrates to defined intracellular locations. Gravin, an AKAP that targets PKA, protein kinase C (PKC) and protein phosphatase 2B (PP2B) to β2‐ARs, is involved in the modulation of the desensitization / resensitization cycle of β2‐ARs by facilitating PKA‐dependent phosphorylation and scaffolding of the β2‐AR complex. Thus, disruption of gravin's scaffolding action might prove beneficial to restore cardiac contractility during heart failure. In our studies, we used isoproterenol to chronically stimulate the β‐ARs to induce heart failure. We found that gravin‐t/t mice, harboring the truncated non‐functional gravin, leads to restriction of receptor desensitization during chronic β‐AR stimulation, due to loss in the assembly of the desensitization complex mediated by gravin's scaffolding. The β‐AR density is significantly higher in gravin‐t/t mice than wild‐type animals after 2 weeks of isoproterenol treatment. This decrease in the desensitization leads to the availability of more receptors on the heart to mediate chronotropy, ionotropy and lusitropy. Together, gravin‐t/t mice exhibited enhanced cardiac function in the presence of chronic β‐AR stimulation. PKA‐dependent substrates including cardiac troponin I (cTnI), phospholamban (PLB), and cardiac myosin binding protein C (cMyBPC), which show aberration activation patterns during heart failure, had normal phosphorylation levels in the gravin‐t/t mice, compared to the wild‐type mice. Gravin‐t/t mice also displayed enhanced myofilaments sensitivity to calcium compared to the wild‐type mice. Our results indicate that gravin plays an important role in regulating the β‐ AR pathway and disruption of its scaffolding augments cardiac function. Thus, blocking of gravin's scaffolding can be further explored as a potential therapeutic target for heart failure.Support or Funding InformationResearch reported in this poster was supported by the NHLBI institute of NIH under Award Number R01HL085487 (to B.K.M.) and R15HL124458 (to B.K.M.). This project was also supported by the Mouse Phenotyping Core at Baylor College of Medicine with funding from the NIH (U54 HG006348).