Beyond the Cardiomyocyte: Consideration of HIPPO Pathway Cell-Type Specificity.

Abstract

Increasing interest in the HIPPO signaling pathway has stemmed largely from its ability to modulate cardioprotection and heart regeneration after injury, responses originating from manipulation within the cardiomyocyte. This viewpoint discusses the need for definitive understanding of HIPPO pathway function in cardiac nonmyocytes and highlights the necessity of considering cell-type specificity for effective therapeutic targeting of the HIPPO pathway in cardiovascular disease. The HIPPO pathway is a highly conserved kinase cascade that determines organ size by regulating cell survival, proliferation, and differentiation. On activation, the core components of the pathway, MST (mammalian sterile 20-like kinase) 1/2, SAV1 (salvador 1), LATS (large tumor suppressor kinase) 1/2, and MOB1 (Mps one binder kinase activator-like 1), serve to phosphorylate and repress activity of the transcriptional cofactors YAP (Yes-associated protein) and TAZ (transcriptional coactivator with a PDZ-binding domain). When HIPPO is inhibited, YAP/TAZ cytosolic retention is relinquished, allowing for nuclear localization and association with multiple transcription factors, the most established being the TEAD (TEA domain) family (Figure 1). Investigation of the HIPPO pathway in the heart has garnered increased attention during the past decade and justifiably so. HIPPO is fundamental in maintaining adult heart homeostasis and modulating responses to injury. To date, the majority of studies investigating HIPPO signaling in the heart have focused on the cardiomyocyte. In response to myocardial infarction or pressure overload stress, the core HIPPO kinase MST1 is activated in cardiomyocytes. MST1 signals through canonical (to restrain YAP) and noncanonical (to antagonize BCL-XL [B-cell lymphoma-extra large] and Beclin1) mechanisms resulting in the inhibition of cardiomyocyte proliferation and autophagy and the enhancement of cell death.1–3 Conversely, HIPPO pathway inhibition limits injury and promotes tissue regeneration through YAP-dependent increases in cardiomyocyte proliferation and survival.4 As a result, interventions that activate cardiomyocyte …