Key result
Myocardium-specific overexpression of RKIP induced major symptoms of heart failure and sensitized the AT1 receptor, whereas dominant-negative GRK2-K220R was cardioprotective.
Why the study?
GRK2 inhibition is an emerging treatment approach for heart failure, prompting investigation into its cardioprotective mechanisms.
Does myocardium-specific expression of RKIP or GRK2-K220R alter cardiac function and AT1 receptor signaling in transgenic mice?
Does myocardium-specific expression of RKIP or GRK2-K220R alter cardiac function and AT1 receptor signaling in transgenic mice?
RKIP induces heart failure symptoms by sensitizing the AT1 receptor, whereas the dominant-negative GRK2-K220R mutant is cardioprotective, indicating that different GRK2 inhibition strategies have divergent cardiac effects.
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, eight-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.
No takes yet. Share an insight, caveat, or question.
Wolf et al. (2019) studied Heart failure. RKIP overexpression vs. Non-transgenic mice was evaluated on Left ventricular ejection fraction and development of heart failure symptoms. Myocardium-specific overexpression of RKIP induced major symptoms of heart failure and sensitized the AT1 receptor, whereas dominant-negative GRK2-K220R was cardioprotective.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: