Paroxetine-mediated GRK2 inhibition reverses cardiac dysfunction and remodeling after myocardial infarction.
Heart failure (HF) is a disease of epidemic proportion and is associated with exceedingly high health care costs. G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptor (GPCR) kinase 2 (GRK2), which is up-regulated in the failing human heart, appears to play a critical role in HF progression in part because enhanced GRK2 activity promotes dysfunctional adrenergic signaling and myocyte death. Recently, we found that the selective serotonin reuptake inhibitor (SSRI) paroxetine could inhibit GRK2 with selectivity over other GRKs. Wild-type mice were treated for 4 weeks with paroxetine starting at 2 weeks after myocardial infarction (MI). These mice were compared with mice treated with fluoxetine, which does not inhibit GRK2, to control for the SSRI effects of paroxetine. All mice exhibited similar left ventricular (LV) dysfunction before treatment; however, although the control and fluoxetine groups had continued degradation of function, the paroxetine group had considerably improved LV function and structure, and several hallmarks of HF were either inhibited or reversed. Use of genetically engineered mice indicated that paroxetine was working through GRK2 inhibition. The beneficial effects of paroxetine were markedly greater than those of β-blocker therapy, a current standard of care in human HF. These data demonstrate that paroxetine-mediated inhibition of GRK2 improves cardiac function after MI and represents a potential repurposing of this drug, as well as a starting point for innovative small-molecule GRK2 inhibitor development.
Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA. Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
Sarah M
SM
Schumacher
Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA.
Erhe
E
Gao
Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, PA 19140, USA.
Weizhong
W
Zhu
Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, PA 19140, USA.
Xiongwen
X
Chen
Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA. Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
J Kurt
JK
Chuprun
Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, PA 19140, USA.
Arthur M
AM
Feldman
Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.
John J G
JJ
Tesmer
Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA. Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA 19140, USA. walter.koch@temple.edu.
Walter J
WJ
Koch
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D005355:Fibrosis; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006333:Heart Failure / Q000150:complications / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000150:complications / Q000503:physiopathology*; D009206:Myocardium / Q000473:pathology; D017374:Paroxetine / Q000494:pharmacology*; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D057170:Translational Research, Biomedical; D020257:Ventricular Remodeling / Q000187:drug effects*
D000319:Adrenergic beta-Antagonists; D011943:Receptors, Adrenergic, beta; D017374:Paroxetine; C496568:GRK2 protein, mouse; D054769:G-Protein-Coupled Receptor Kinase 2