Hippo Deficiency Leads to Cardiac Dysfunction Accompanied by Cardiomyocyte Dedifferentiation During Pressure Overload

Abstract

The Hippo pathway plays an important role in determining organ size through regulation of cell proliferation and apoptosis. Hippo inactivation and consequent activation of YAP (Yes-associated protein), a transcription cofactor, have been proposed as a strategy to promote myocardial regeneration after myocardial infarction. However, the long-term effects of Hippo deficiency on cardiac function under stress remain unknown. Objective: We investigated the long-term effect of Hippo deficiency on cardiac function in the presence of pressure overload (PO). Methods and Results: We used mice with cardiac-specific homozygous knockout of WW45 (WW45cKO), in which activation of Mst1 (Mammalian sterile 20-like 1) and Lats2 (large tumor suppressor kinase 2), the upstream kinases of the Hippo pathway, is effectively suppressed because of the absence of the scaffolding protein. We used male mice at 3 to 4 month of age in all animal experiments. We subjected WW45cKO mice to transverse aortic constriction for up to 12 weeks. WW45cKO mice exhibited higher levels of nuclear YAP in cardiomyocytes during PO. Unexpectedly, the progression of cardiac dysfunction induced by PO was exacerbated in WW45cKO mice, despite decreased apoptosis and activated cardiomyocyte cell cycle reentry. WW45cKO mice exhibited cardiomyocyte sarcomere disarray and upregulation of TEAD1 (transcriptional enhancer factor) target genes involved in cardiomyocyte dedifferentiation during PO. Genetic and pharmacological inactivation of the YAP-TEAD1 pathway reduced the PO-induced cardiac dysfunction in WW45cKO mice and attenuated cardiomyocyte dedifferentiation. Furthermore, the YAP-TEAD1 pathway upregulated OSM (oncostatin M) and OSM receptors, which played an essential role in mediating cardiomyocyte dedifferentiation. OSM also upregulated YAP and TEAD1 and promoted cardiomyocyte dedifferentiation, indicating the existence of a positive feedback mechanism consisting of YAP, TEAD1, and OSM. Conclusions: Although activation of YAP promotes cardiomyocyte regeneration after cardiac injury, it induces cardiomyocyte dedifferentiation and heart failure in the long-term in the presence of PO through activation of the YAP-TEAD1-OSM positive feedback mechanism.

Yes-associated protein (YAP) mediates adaptive cardiac hypertrophy in response to pressure overload

“…S2, C, D, and E). In a recent study (19), we found that YAP is inactivated during the decompensated phase of cardiac hypertrophy. Thus, we sought to determine the functional significance of cardiac YAP activation during the compensated phase of PO.…”

Single-cell analysis of murine fibroblasts identifies neonatal to adult switching that regulates cardiomyocyte maturation

“…Cardiac maturity is central to heart development and disease. It is generally accepted that progressive dedifferentiation of cardiomyocyte, and thus loss of CM identity, is the hallmark molecular event in cardiac hypertrophy 40,41 . By contrast, much less is understood about its microenvironmental setting, especially with regard to how the microenvironment transforms in disease, and subsequently translates into deteriorations in CMs.…”

Combining Nanomaterials and Developmental Pathways to Design New Treatments for Cardiac Regeneration: The Pulsing Heart of Advanced Therapies

“…Although progresses in myocardial regeneration in Hippo-deficient heart was reported by Tao et al (2016), restoration of overall cardiac function by tuning Hippo-pathway components seems to be a more complex task, which requires additional research and validation. In fact, Ikeda et al (2019) described that long term activation of YAP facilitates the progression of heart failure, in response to pressure overload, in transgenic mice model lacking WW45 Hippo component. Despite homozygous knockout of WW45 (WW45cKO) in Zeng et al, 2003;Allijn et al, 2017 LDL-C, low density lipoprotein-C; CHF, congestive heart failure; Increlex1, mecasermin, a human recombinant IGF-1 analog; IPLEX1, mecasermin rinfabate, a binary protein complex of human recombinant IGF-1 and human recombinant IGBP-3; IGBP-3, insulin-like growth factor binding protein-3; HO-1, heme oxygenase-1; TGFβ, transforming growth factor β; GSK3, glycogen synthase kinase-3.…”