Pak1 overexpression is associated with mild concentric cardiac remodeling and favorable systolic and diastolic functional indices in transgenic mice.

Abstract

Background: p21-activated kinase 1 (Pak1) is a serine/threonine kinase implicated in cardioprotection, calcium handling, and excitation-contraction coupling. However, the effects of Pak1 gain- and loss-of-function on cardiac performance remain incompletely understood. Here, we characterized baseline overall cardiac performance in cardiac-specific Pak1 transgenic (TG) and knockout (KO) mice using advanced echocardiography and invasive hemodynamic assessments.

Methods: Adult wild type (WT), Pak1 TG, and Pak1 KO mice, aged 7-11 months, underwent comprehensive phenotyping, including M-mode echocardiography, pulsed-wave and tissue Doppler imaging, speckle-tracking echocardiography (STE)-based strain analysis, invasive left ventricular pressure measurements, Western blot analysis, and histological evaluation using hematoxylin and eosin and Masson's trichrome staining. In addition, WT and Pak1 TG mice aged 20-22 months were studied to assess persistence of the TG phenotype with aging.

Results: M-mode echocardiography showed that Pak1 TG mice exhibited concentric LV remodeling, characterized by increased wall thickness and reduced chamber dimensions compared with KO and WT controls. Histological analysis revealed greater cardiomyocyte cross-sectional area and width in TG mice than in KO mice, whereas WT values were intermediate and did not differ significantly from TG. Masson's trichrome staining detected no significant difference in myocardial fibrosis between TG and WT hearts under the present sampling conditions. Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) expression was not elevated in TG hearts. TG hearts exhibited higher fractional shortening and increased global longitudinal, radial, and circumferential strain, indicating increased echocardiographic indices of systolic function. Invasive hemodynamics showed higher +dP/dt _max without a significant difference in aortic blood pressure, although these findings do not establish load-independent intrinsic contractility. Diastolic indices also differed, including increased diastolic strain rates, shorter IVRT, lower Tau, and reduced myocardial performance index, whereas E/e' was unchanged. Similar remodeling and functional indices were observed in aged TG mice, although the cross-sectional design does not establish preservation with aging. Pak1 KO mice showed modestly reduced systolic indices with preserved diastolic indices.

Conclusions: Pak1 overexpression is associated with concentric LV remodeling and favorable systolic and diastolic functional indices. These findings support further investigation of Pak1-dependent mechanisms and its role in cardiac disease.