In heart failure therapy, it is generally assumed that attempts to produce a long-term increase in cardiac contractile force are almost always accompanied by structural and functional damage. Here we show that modest overexpression of the Raf kinase inhibitor protein (RKIP), encoded by Pebp1 in mice, produces a well-tolerated, persistent increase in cardiac contractility that is mediated by the β1-adrenoceptor (β1AR). This result is unexpected, as β1AR activation, a major driver of cardiac contractility, usually has long-term adverse effects. RKIP overexpression achieves this tolerance via simultaneous activation of the β2AR subtype. Analogously, RKIP deficiency exaggerates pressure overload-induced cardiac failure. We find that RKIP expression is upregulated in mouse and human heart failure, indicative of an adaptive role for RKIP. Pebp1 gene transfer in a mouse model of heart failure has beneficial effects, suggesting a new therapeutic strategy for heart failure therapy.

Extracellular signal-regulated kinases 1 and 2 (ERK1/2) are central mediators of cardiac hypertrophy and are discussed as potential therapeutic targets. However, direct inhibition of ERK1/2 leads to exacerbated cardiomyocyte death and impaired heart function. We have previously identified ERK Thr188 autophosphorylation as a regulatory phosphorylation of ERK1/2 that is a key factor in cardiac hypertrophy. Here, we investigated whether interference with ERK Thr188 phosphorylation permits the impairment of ERK1/2-mediated cardiac hypertrophy without increasing cardiomyocyte death. The impact of ERK Thr188 phosphorylation on cardiomyocyte hypertrophy and cell survival was analyzed in isolated cells and in mice using the mutant ERK2 T188A , which is dominant-negative for ERK Thr188 signaling. ERK2 T188A efficiently attenuated cardiomyocyte hypertrophic responses to phenylephrine and to chronic pressure overload, but it affected neither antiapoptotic ERK1/2 signaling nor overall physiological cardiac function. In contrast to its inhibition of pathological hypertrophy, ERK2 T188A did not interfere with physiological cardiac growth occurring with age or upon voluntary exercise. A preferential role of ERK Thr188 phosphorylation in pathological types of hypertrophy was also seen in patients with aortic valve stenosis: ERK Thr188 phosphorylation was increased 8.5 ± 1.3-fold in high-gradient, rapidly progressing cases (≥40 mmHg gradient), whereas in low-gradient, slowly progressing cases, the increase was not significant. Because interference with ERK Thr188 phosphorylation (i) inhibits pathological hypertrophy and (ii) does not impair antiapoptotic ERK1/2 signaling and because ERK Thr188 phosphorylation shows strong prevalence for aortic stenosis patients with rapidly progressing course, we conclude that interference with ERK Thr188 phosphorylation offers the possibility to selectively address pathological types of cardiac hypertrophy.MAPK | apoptosis | GPCRs C ardiac hypertrophy has been identified as an independent risk factor of diastolic dysfunction, heart failure, arrhythmias, and sudden death (1). Various triggers initiate cardiac hypertrophy, but the type of trigger has been identified as decisive for an adaptive vs. a maladaptive outcome of cardiac hypertrophy. Whereas cardiovascular diseases such as hypertension, aortic stenosis, or myocardial infarction generally induce a pathological type of hypertrophy, chronic physical exercise or postnatal cardiac growth entail a compensatory and physiological type of hypertrophy. In contrast to physiological hypertrophy, pathological hypertrophy is characterized by accumulation of interstitial collagen and cell death, which both have been shown to contribute to increased cardiovascular risk (2-5). Therefore, it would be of great therapeutic interest to prevent pathological hypertrophy; however, such prevention requires a fine balance between inhibition of maladaptive and preservation of compensatory adaptive hypertrophy.Hypertrophic stimuli are mediated via several intracell...

Background: Raf kinase inhibitor protein (RKIP) is a regulator of several distinct kinases, including Raf1 and G proteincoupled receptor kinase 2 (GRK2). Results: Protein kinase C-mediated phosphorylation of RKIP triggers dimer formation of RKIP, which enables RKIP to switch specificity between Raf1 and GRK2. Conclusion: Phosphorylation-dependent dimerization of RKIP coordinates specific interactions with Raf1 and GRK2. Significance: Control switches in a kinase regulator permit specific control of multiple kinase signaling pathways and their downstream functions.