Research ArticleHeart Failure

Paroxetine-mediated GRK2 inhibition reverses cardiac dysfunction and remodeling after myocardial infarction

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Science Translational Medicine  04 Mar 2015:
Vol. 7, Issue 277, pp. 277ra31
DOI: 10.1126/scitranslmed.aaa0154

Taking antidepressants to heart

Drug repurposing—extending currently Food and Drug Administration (FDA)–approved drugs to treat additional diseases—has both economic and safety advantages over new drug development. The selective serotonin reuptake inhibitor (SSRI) paroxetine, which is used as an antidepressant, has been shown to selectively inhibit G protein (heterotrimeric guanine nucleotide–binding protein)–coupled receptor kinase 2 (GRK2), which is thought to contribute to heart failure progression. Now Schumacher et al. report that paroxetine can block or even reverse heart damage after myocardial infarction in a mouse model. These affects are separate from its SSRI functions and are further enhanced in the presence of current standard-of-care β-blockers. If these data hold true in humans, paroxetine therapy could be an additional or even additive strategy for treating heart failure.


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.

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