Disruption of Gravin’s Scaffolding Protects against Isoproterenol Induced Heart Failure in Mice



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Impairment in the β adrenergic pathway is one of the hallmark pathologies of heart failure. This vicious cycle starts with chronic stimulation of the βARs during heart failure causing their severe desensitization and down regulation. This causes further downstream molecular dysfunction leading to worsening of heart failure. Gravin is a scaffolding protein belonging to the family of A Kinase Anchoring Proteins and makes a very attractive target for heart failure. As an AKAP, gravin binds to multiple proteins such as PKA, PKC, β2ARs, PDE4D3, PP2B etc. and is involved in the modulation of the desensitization and resensitization cycle of β2 ARs indicating that disruption of gravin’s scaffolding action might prove beneficial in heart failure. In our studies we used isoproterenol to chronically stimulate the βARs to induce heart failure. We found that gravin t/t mice harboring the truncated non functional gravin leads to restriction of the extent of receptor desensitization during chronic βAR stimulation, due to loss in the assembly of the desensitization machinery mediated by the scaffolding of the gravin. The βAR density is significantly higher in the gravin t/t mice than the WT animals after 2 weeks of isoproterenol treatment. This decrease in the desensitization leads to the availability of more receptors on the heart to mediate the chronotropy, ionotropy and lusitropy, which translated into the gravin t/t animals exhibiting enhanced cardiac function in face of the chronic stimulation. Major proteins such as cTnI, PLB, cMyBPC etc., which show aberration activation patterns during heart failure had normal phosphorylation levels in the gravin t/t mice, compared to the WT mice. Gravin t/t mice also displayed enhanced myofilaments sensitivity to calcium compared to the WT mice. Our results indicate that gravin plays an important role in regulating the βAR pathway and disruption of its scaffolding augments cardiac function. Hence blocking of gravin’s scaffolding can be further explored as a potential therapeutic target for heart failure.



Gravin, Heart failure, AKAP 250, AKAP 12, Carvedilol, Bisoprolol, ICI115881


Portions of this document appear in: Guillory, Ashley N., Xing Yin, Cori S. Wijaya, Andrea C. Diaz Diaz, Abeer Rababa’h, Sonal Singh, Fatin Atrooz, Sakthivel Sadayappan, and Bradley K. McConnell. "Enhanced cardiac function in Gravin mutant mice involves alterations in the β-adrenergic receptor signaling cascade." PloS one 8, no. 9 (2013): e74784.