Regulation of Cardiac Hypertrophic Signaling by Prolyl Isomerase Pin1

Abstract

Rationale Cardiac hypertrophy results from the complex interplay of differentially regulated cascades based upon the phosphorylation status of involved signaling molecules. While numerous critical regulatory kinases and phosphatases have been identified in the myocardium, the intracellular mechanism for temporal regulation of signaling duration and intensity remains obscure. In the non-myocyte context, control of folding, activity, and stability of proteins is mediated by the prolyl isomerase Pin1, but the role of Pin1 in the heart is unknown. Objective To establish the role of Pin1 in the heart. Methods and Results Here we show that either genetic deletion or cardiac over-expression of Pin1 blunts hypertrophic responses induced by transaortic constriction and consequent cardiac failure in vivo. Mechanistically, we find that Pin1 directly binds to Akt, MEK and Raf-1 in cultured cardiomyocytes following hypertrophic stimulation. Furthermore, loss of Pin1 leads to diminished hypertrophic signaling of Akt and MEK, while over-expression of Pin1 increases Raf-1 phosphorylation on the auto-inhibitory site Ser259 leading to reduced MEK activation. Conclusions Collectively, these data support a role for Pin1 as a central modulator of the intensity and duration of two major hypertrophic signaling pathways, thereby providing a novel target for regulation and control of cardiac hypertrophy.

Differential Regulation of Cellular Senescence and Differentiation by Prolyl Isomerase Pin1 in Cardiac Progenitor Cells

“…Mice were anesthetized using 1-2% isoflurane and echocardiography was performed using Vevo770 High Resolution In Vivo Micro-Imaging System (Visual Sonics) as described in Ref. 4. B-mode echocardiography of the left ventricle was recorded in a parasternal long-axis view and left ventricle end-diastolic volume, and left ventricle end-systolic volumes were obtained.…”

“…Immunoblot Analysis-Whole cell lysates were resolved by SDS-polyacrylamide gel electrophoresis and immunoblot analyses were performed as described (4). Immunoblot band intensities were measured using ImageJ software (NIH) (4).…”

“…However, the efficiency of CPC-mediated regeneration may be further augmented by delineating molecular mechanisms of endogenous cardiac repair and enhancing pro-survival pathways that maintain the youthfulness of stem cells, whereas also increasing differentiation. Prolyl isomerase Pin1 is one such molecule that functions as a molecular orchestrator of signaling yielding multifarious beneficial effects (4).…”

“…Pin1 regulates the stability, activity, and subcellular localization of proteins by controlling the three-dimensional structure of phosphoproteins through alterations of cis-trans isomerization upon recognition of a major regulatory phosphorylation motif (Ser/Thr-Pro) (4). Pin1 is expressed in proliferating cells and exerts wide ranging influence upon multiple regulatory molecules of the mitotic processes including cyclins and cell cycle inhibitors such as Cyclin D, Cyclin B, Cyclin E, p53, and retinoblastoma (Rb) to name a few (5)(6)(7)(8).…”

Structure and function of the human parvulins Pin1 and Par14/17

“…Subsequent reactions are often the initiation or prevention of PTM processes such as ubiquitination (Siepe and Jentsch, 2009) or conformer-specific protein-protein interactions . Depending on this outcome Pin1 could enhance (Lee et al, 2009b) or weaken Eckerdt et al, 2005;Luo et al, 2010;Khanal et al, 2012) protein stability and influence protein turn-over; it can drive protein cascades in signaling events (Keune et al, 2013;Toko et al, 2013;Antonelli et al, 2014;So and Oh, 2015;Rustighi et al, 2017) or regulate metabolic processes such as the insulin dependent glucose uptake (Nakatsu et al, 2009).…”