Pak1 as a Novel Therapeutic Target for Antihypertrophic Treatment in the Heart

Abstract

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.

Polycomb-mediated loss of microRNA let-7c determines inflammatory macrophage polarization via PAK1-dependent NF-κB pathway

“…PAK1 fl/fl mice were constructed by homologous recombination in embryonic stem cells using standard methods as described previously. 47 Mice with myeloid cell-specific deletion of PAK1 (PAK1 þ / þ Mx1-Cre genotype were given i.p. injection of poly(I:C) at a dose of 200 mg per mouse three times in 5 days to induce deletion, and 2 weeks later mice were used for experiments.…”

P21 activated kinases

“…Thus, Pak1 acts as an anti-hypertrophic agent, revealing a link between Pak1 and ventricular hypertrophy, and indicating that Pak1 knockouts are more susceptible to heart failure when the heart is subjected to pressure overload. 72,79 Deletion of PAK4 leads to embryonic lethality, but among the different abnormalities in the PAK4 knockout embryos, is a dramatic abnormality in heart development. 76 These include thinning of the myocardial walls of the bulbus cordis and the ventricle, and severe dilation and distortion of the sinus venosus region.…”

Smad3 Couples Pak1 With the Antihypertrophic Pathway Through the E3 Ubiquitin Ligase, Fbxo32

“…Cardiomyocyte-specific male mouse models include Pak1 knockout (Pak1 cKO ) mice and its control counterpart homozygous Pak1 flox (f/f) mice 17 ; overexpression of constitutively active Pak1 (Pak1 cTG ) mice and its control counterpart nontransgenic mice. Both mouse models and their control counterparts were subjected to transverse aortic constriction (TAC).…”

“…17 To directly examine Pak1 activation in the heart, mice with cardiac-specific overexpression of constitutively active Pak1 driven by an α-myosin heavy chain promoter (Pak1 cTG ) were generated ( Figure S1 in the online-only Data Supplement). Pak1 cTG mice were viable, fertile, and developed to adulthood.…”

“…11,[14][15][16] P21-activated kinase 1 (Pak1) has been discovered as an important serine/threonine kinase with crucial functions in the heart. [17][18][19] It belongs to the group I Pak family and is activated by GTP-bound Cdc42/Rac1 GTPases. 20 Studies by Liu et al 17,21 reported on the antihypertrophic property of Pak1 through Abstract-Pathological cardiac hypertrophy is regarded as a critical intermediate step toward the development of heart failure.…”