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


OBJECTIVE
We sought to investigate small molecule Gbetagamma inhibition in HF.


RESULTS
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).


CONCLUSIONS
These data suggest a promising therapeutic role for small molecule inhibition of pathological Gbetagamma signaling in the treatment of HF.
Casey
Liam M
LM
Aab Cardiovascular Research Institute and Department of Medicine, University of Rochester School of Medicine and Dentistry, NY, USA.
Pistner
Andrew R
AR
Belmonte
Stephen L
SL
Migdalovich
Dmitriy
D
Stolpnik
Olga
O
Nwakanma
Frances E
FE
Vorobiof
Gabriel
G
Dunaevsky
Olga
O
Matavel
Alessandra
A
Lopes
Coeli M B
CM
Smrcka
Alan V
AV
Blaxall
Burns C
BC
D000818:Animals; D003510:Cyclohexanes / Q000494:pharmacology / Q000627:therapeutic use; D018450:Disease Progression; D005260:Female; D044387:GTP-Binding Protein beta Subunits / Q000037:antagonists & inhibitors* / Q000378:metabolism; D044388:GTP-Binding Protein gamma Subunits / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018922:HL-60 Cells; D006333:Heart Failure / Q000378:metabolism / Q000517:prevention & control*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014966:Xanthenes / Q000494:pharmacology / Q000627:therapeutic use; D014981:Xenopus
D003510:Cyclohexanes; D044387:GTP-Binding Protein beta Subunits; D044388:GTP-Binding Protein gamma Subunits; C509953:M119 compound; D014966:Xanthenes; C007820:gallein