Disruption of mechanical stress in extracellular matrix is related to Stanford type A aortic dissection through down-regulation of Yes-associated protein

Abstract

In this study, we assessed whether the down-regulation of Yes-associated protein (YAP) is involved in the pathogenesis of extracellular matrix (ECM) mechanical stress-induced Stanford type A aortic dissection (STAAD). Human aortic samples were obtained from heart transplantation donors as normal controls and from STAAD patients undergoing surgical replacement of the ascending aorta. Decreased maximum aortic wall velocity, ECM disorders, increased VSMC apoptosis, and YAP down-regulation were identified in STAAD samples. In a mouse model of STAAD, YAP was down-regulated over time during the development of ECM damage, and increased VSMC apoptosis was also observed. YAP knockdown induced VSMC apoptosis under static conditions in vitro, and the change in mechanical stress induced YAP down-regulation and VSMC apoptosis. This study provides evidence that YAP down-regulation caused by the disruption of mechanical stress is associated with the development of STAAD via the induction of apoptosis in aortic VSMCs. As STAAD is among the most elusive and life-threatening vascular diseases, better understanding of the molecular pathogenesis of STAAD is critical to improve clinical outcome.

The role of Hippo/yes‐associated protein signalling in vascular remodelling associated with cardiovascular disease

“…A similar phenomenon was observed in a mouse BAPN‐induced Stanford type A aortic dissection model (Jiang et al, ). YAP deficiency increased VSMC apoptosis under static conditions in vitro , and the change in mechanical stress induced YAP down‐regulation and VSMC apoptosis (Jiang et al, ).…”

MRTF-A promotes angiotensin II-induced inflammatory response and aortic dissection in mice

“…The involvement of MRTF-A in AD pathogenesis was further supported by the fact that CCG-203971, an inhibitor of MRTF-A, prevented the AngII-induced AD development. As recent studies indicated the involvement of inflammatory response [5,6,22,23] and apoptosis [19,24] in AD pathogenesis, these data suggested that MRTF-A promotes AD by regulating inflammatory and apoptotic responses. Gene annotation enrichment analysis was performed for the genes with higher expression in MRTF-A-KO aorta compared to wild-type (WT) aorta, among the AngII-suppressed genes.…”

“…Apoptosis of aortic cells, mainly SMCs, is observed both in human AD and mouse model of AD [24], and tightly coupled with the phenotype of AD in mouse model [19,27,28]. Causative involvement of apoptosis in aortopathy was demonstrate by the suppression of SMC apoptosis and thoracic aortic aneurysm by a caspase inhibitor in a mouse model of Marfan syndrome [29].…”

TAZ Is Related to Postoperative In-Hospital Mortality of Acute Type A Aortic Dissection

“…As a result, more easily measurable and precise biomarkers are needed for aortic surgeons to precisely evaluate the postoperative in-hospital mortality of patients and make the best choices for their patients. TAZ exists in most human tissue, and its functional role is critical in the cardiovascular system (8,20,21). Our previous study found that Hippo pathway expression played a key role in hypertrophic cardiomyopathy (22).…”

“…WW domain-containing transcription regulator protein 1 (TAZ) is ubiquitous in the human body and mainly found downstream of the Hippo pathway, which regulates many fundamental biological processes (7). Our previous research focused on the molecular pathogenesis of ATAAD and found that altered mechanical stress induced the change of Hippo pathway, which contributes to ATAAD development (8). As TAZ play important roles in the development of ATAAD, they might also be related to postoperative mortality of ATAAD.…”