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Circ Res August 20, 2010; 107 (4): 532-9.

Small molecule disruption of G beta gamma signaling inhibits the progression of heart failure.

Casey LM , Pistner AR , Belmonte SL , Migdalovich D , Stolpnik O , Nwakanma FE , Vorobiof G , Dunaevsky O , Matavel A , Lopes CM , Smrcka AV , Blaxall BC .

Excess signaling through cardiac Gbetagamma subunits is an important component of heart failure (HF) pathophysiology. They recruit elevated levels of cytosolic G protein-coupled receptor kinase (GRK)2 to agonist-stimulated beta-adrenergic receptors (beta-ARs) in HF, leading to chronic beta-AR desensitization and downregulation; these events are all hallmarks of HF. Previous data suggested that inhibiting Gbetagamma signaling and its interaction with GRK2 could be of therapeutic value in HF. We sought to investigate small molecule Gbetagamma inhibition in HF. We recently described novel small molecule Gbetagamma inhibitors that selectively block Gbetagamma-binding interactions, including M119 and its highly related analog, gallein. These compounds blocked interaction of Gbetagamma and GRK2 in vitro and in HL60 cells. Here, we show they reduced beta-AR-mediated membrane recruitment of GRK2 in isolated adult mouse cardiomyocytes. Furthermore, M119 enhanced both adenylyl cyclase activity and cardiomyocyte contractility in response to beta-AR agonist. To evaluate their cardiac-specific effects in vivo, we initially used an acute pharmacological HF model (30 mg/kg per day isoproterenol, 7 days). Concurrent daily injections prevented HF and partially normalized cardiac morphology and GRK2 expression in this acute HF model. To investigate possible efficacy in halting progression of preexisting HF, calsequestrin cardiac transgenic mice (CSQ) with extant HF received daily injections for 28 days. The compound alone halted HF progression and partially normalized heart size, morphology, and cardiac expression of HF marker genes (GRK2, atrial natriuretic factor, and beta-myosin heavy chain). These data suggest a promising therapeutic role for small molecule inhibition of pathological Gbetagamma signaling in the treatment of HF.

PubMed ID: 20576935
PMC ID: PMC2924955
Article link: Circ Res
Grant support: GM081772 NIGMS NIH HHS , R01HL084087 NHLBI NIH HHS , R01HL089885 NHLBI NIH HHS , R01HL091475 NHLBI NIH HHS , T32GM07356 NIGMS NIH HHS , R01 GM081772-03 NIGMS NIH HHS , R01 GM081772-04 NIGMS NIH HHS , R01 HL089885-02 NHLBI NIH HHS , R01 HL089885-04 NHLBI NIH HHS , R01 HL091475-01A1 NHLBI NIH HHS , R01 HL091475-02 NHLBI NIH HHS , T32 GM007356-35 NIGMS NIH HHS , R01 HL084087-01A2 NHLBI NIH HHS , R01 HL091475-03 NHLBI NIH HHS , R01 GM081772 NIGMS NIH HHS , R01 HL084087 NHLBI NIH HHS , R01 HL089885 NHLBI NIH HHS , R01 HL091475 NHLBI NIH HHS , T32 GM007356 NIGMS NIH HHS

GO Terms: G-protein coupled receptor kinase activity [+]

Disease Ontology terms: congestive heart failure
Blaxall, 2003, Pubmed [+]

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