Abstract
Inhibition of the G-protein-coupled receptor kinase 2 (GRK2) is an emerging treatment approach for heart failure. Therefore, cardio-protective mechanisms induced by GRK2 inhibition are under investigation. We compared two different GRK2 inhibitors, i.e., (i) the dual-specific GRK2 and raf kinase inhibitor protein, RKIP, and (ii) the dominant-negative GRK2-K220R mutant. We found that RKIP induced a strong sensitization of Gq/11-dependent, heart failure-promoting angiotensin II AT1 receptor signaling. The AT1-sensitizing function of RKIP was mediated by the RKIP-GRK2 interaction because the RKIP-S153V mutant, which does not interact with GRK2, had no effect on AT1-stimulated signaling. In contrast, GRK2-K220R significantly inhibited the AT1-stimulated signal. The in vivo relevance of these major differences between two different approaches of GRK2 inhibition was analyzed by generation of transgenic mice with myocardium-specific expression of RKIP and GRK2-K220R. Our results showed that a moderately increased cardiac protein level of RKIP was sufficient to induce major symptoms of heart failure in aged, 8-months-old RKIP-transgenic mice in two different genetic backgrounds. In contrast, GRK2-K220R protected against chronic pressure overload-induced cardiac dysfunction. The AT1 receptor contributed to RKIP-induced heart failure because treatment with the AT1 receptor antagonist, losartan, retarded symptoms of heart failure in RKIP-transgenic mice. Thus, sensitization of the heart failure-promoting AT1 receptor by the RKIP-GRK2 interaction contributes to heart failure whereas dominant-negative GRK2-K220R is cardioprotective. Because RKIP is up-regulated on cardiac biopsy specimens of heart failure patients, the deduced heart failure-promoting mechanism of RKIP could also be relevant for the human disease.
Highlights
The family of G-protein-coupled receptor kinases (GRKs) initiates the process of signal desensitization by phosphorylation of G-protein-coupled receptors [1, 2]
We investigated the impact of RKIP on signaling mediated by the heart failure-promoting, Gq/11-coupled angiotensin II AT1 receptor
This signal sensitization of the AT1 receptor was mediated by the RKIP-G-protein-coupled receptor kinase 2 (GRK2) interaction because the RKIP-S153V mutant, which cannot switch from Raf1 to GRK2 [19], had no effect on the AT1 signal (Figure 1B)
Summary
The family of G-protein-coupled receptor kinases (GRKs) initiates the process of signal desensitization by phosphorylation of G-protein-coupled receptors [1, 2]. Mechanisms of RKIP-Induced Heart Failure of exaggerated GRK2 activity in experimental models of heart failure is cardio-protective [4,5,6,7,8]. Based on these data, inhibition of GRK2 appears as a promising treatment approach of heart failure [9, 10]. Experimental evidence indicates that a major cardioprotective mechanism induced by GRK2 inhibition relies on resensitization of desensitized beta-adrenoceptors in heart failure [9, 10]. Prevention of cardiomyocyte death by GRK2 inhibition was partially attributed to enhancement of the prosurvival Raf-Erk pathway [8, 12]
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