Background: The Ca2+-releasing messenger nicotinic acid adenine dinucleotide phosphate (NAADP) acts via lysosomal two-pore channels (TPC2).Results: Tpcn2−/− cardiac myocytes showed reduced acute responses to β-adrenoreceptor stimulation and chronically reduced cardiac hypertrophy and arrhythmogenesis.Conclusion: Acute and chronic effects of cardiac β-adrenoreceptor stimulation depend on NAADP acting via TPC2 in lysosomes.Significance: NAADP/TPC2 signaling pathways offer new strategies for cardiac therapeutics.

Background Stress-induced hypertrophic remodeling is a critical pathogenetic process leading to heart failure. While many signal transduction cascades are demonstrated as important regulators to facilitate the induction of cardiac hypertrophy, the signaling pathways for suppressing hypertrophic remodeling remain largely unexplored. In this study, we identified p21-activated kinase 1 (Pak1) as a novel signaling regulator which antagonizes cardiac hypertrophy. Methods and Results Hypertrophic stress applied to primary neonatal rat cardiomyocytes (NRCMs), or murine hearts caused the activation of Pak1. Analysis of NRCMs expressing constitutively active Pak1 or in which Pak1 was silenced disclosed that Pak1 played an anti-hypertrophic role. To investigate the in vivo role of Pak1 in the heart, we generated mice with a cardiomyocyte-specific deletion of Pak1 (Pak1cko). When subject to 2 weeks of pressure overload, Pak1cko mice compared to controls, developed greater cardiac hypertrophy with attendant blunting of JNK activation, and these knockout mice underwent the transition into heart failure when prolonged stress was applied. In addition, chronic angiotensin II infusion also caused increased cardiac hypertrophy in Pak1cko mice. Moreover, we discovered that the Pak1 activator FTY720, a sphingosine-like analogue, was able to prevent pressure overload-induced hypertrophy in wild-type mice, without compromising their cardiac functions. Meanwhile FTY720 failed to exert such an effect on Pak1cko mice, suggesting that the anti-hypertrophic effect of FTY720 likely acts through Pak1 activation. Conclusions These results, for the first time, establish Pak1 as a novel anti-hypertrophic regulator and suggest that it may be a potential therapeutic target for the treatment of cardiac hypertrophy and heart failure.

This article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc.