Hippo pathway effector Yap promotes cardiac regeneration

Abstract

The adult mammalian heart has limited potential for regeneration. Thus, after injury, cardiomyocytes are permanently lost, and contractility is diminished. In contrast, the neonatal heart can regenerate owing to sustained cardiomyocyte proliferation. Identification of critical regulators of cardiomyocyte proliferation and quiescence represents an important step toward potential regenerative therapies. Yes-associated protein (Yap), a transcriptional cofactor in the Hippo signaling pathway, promotes proliferation of embryonic cardiomyocytes by activating the insulin-like growth factor and Wnt signaling pathways. Here we report that mice bearing mutant alleles of Yap and its paralog WW domain containing transcription regulator 1 ( Taz ) exhibit gene dosage-dependent cardiac phenotypes, suggesting redundant roles of these Hippo pathway effectors in establishing proper myocyte number and maintaining cardiac function. Cardiac-specific deletion of Yap impedes neonatal heart regeneration, resulting in a default fibrotic response. Conversely, forced expression of a constitutively active form of Yap in the adult heart stimulates cardiac regeneration and improves contractility after myocardial infarction. The regenerative activity of Yap is correlated with its activation of embryonic and proliferative gene programs in cardiomyocytes. These findings identify Yap as an important regulator of cardiac regeneration and provide an experimental entry point to enhance this process.

Inhibition of Dipeptidyl Peptidase-4 Impairs Ventricular Function and Promotes Cardiac Fibrosis in High Fat–Fed Diabetic Mice

“…Elevated levels of TGF-b are associated with both fibrosis and cardiac hypertrophy (33,34). We evaluated signaling through canonical and noncanonical mediators of fibrosis and hypertrophy in response to TGF-b, including ERK, GSK-3b/ b-catenin (35), pSMAD2/SMAD2 (36), Akt (37), and YAP (38). Although we did not observe any robust changes in these effectors, these pathways are known to be activated in the short term in response to pressure overload and remain only moderately elevated at later time points (34,39).…”

Pituitary stem cell regulation: who is pulling the strings?

“…The Hippo network has also been implicated in tissue regeneration. Genetically enhanced YAP/TAZ activity in the adult heart stimulates cardiac regeneration after myocardial infarction (Heallen et al 2013, Xin et al 2013. In the intestine, YAP was found indispensable for regeneration of the epithelium by the intestinal stem cells after irradiation (Gregorieff et al 2015).…”

Restoration of YAP activation rescues HL-1 cardiomyocytes from apoptotic death by ethanol

“…One of the vulnerabilities of the heart is its inability to regenerate, even though heart function and systemic circulation are necessary for life. However, the concept that cardiomyocytes in the adult heart do not proliferate has been challenged by recent studies showing that cardiomyocytes can regenerate through transfer with Yes-associated protein (YAP), a transcriptional co-activator (Xin et al, 2013).…”

“…Recent research advances have indicated a central role for YAP in the proliferation, regeneration, and cellsize control of cardiomyocytes (Heallen et al, 2013;Xin et al, 2013;Zhou et al, 2015). In addition to the Hippo kinase pathway that has long been considered the main upstream pathway of YAP, mechanotransduction, which converts mechanical signals from cell-extra cellular matrix (ECM) and cell-cell contact into intracellular signaling pathways via actin tension, has been proposed as another important regulator of YAP (Dupont et al, 2011).…”