TGF-β1 affects cell-cell adhesion in the heart in an NCAM1-dependent mechanism

Abstract

The contractile property of the myocardium is maintained by cell-cell junctions enabling cardiomyocytes to work as a syncytium. Alterations in cell-cell junctions are observed in heart failure, a disease characterized by the activation of Transforming Growth Factor beta 1 (TGFβ1). While TGFβ1 has been implicated in diverse biologic responses, its molecular function in controlling cell-cell adhesion in the heart has never been investigated. Cardiac-specific transgenic mice expressing active TGFβ1 were generated to model the observed increase in activity in the failing heart. Activation of TGFβ1 in the heart was sufficient to drive ventricular dysfunction. To begin to understand the function of this important molecule we undertook an extensive structural analysis of the myocardium by electron microscopy and immunostaining. This approach revealed that TGFβ1 alters intercalated disc structures and cell-cell adhesion in ventricular myocytes. Mechanistically, we found that TGFβ1 induces the expression of neural adhesion molecule 1 (NCAM1) in cardiomyocytes in a p38-dependent pathway, and that selective targeting of NCAM1 was sufficient to rescue the cell adhesion defect observed when cardiomyocytes were treated with TGFβ1. Importantly, NCAM1 was upregulated in human heart samples from ischemic and non-ischemic cardiomyopathy patients and NCAM1 protein levels correlated with the degree of TGFβ1 activity in the human cardiac ventricle. Overall, we found that TGFβ1 is deleterious to the heart by regulating the adhesion properties of cardiomyocytes in an NCAM1-dependent mechanism. Our results suggest that inhibiting NCAM1 would be cardioprotective, counteract the pathological action of TGFβ1 and reduce heart failure severity.

siRNA‐mediated NCAM1 gene silencing suppresses oxidative stress in pre‐eclampsia by inhibiting the p38MAPK signaling pathway

“…Additionally, H/R intervention has been reported to induce p38 activation, thereby results in an upregulation in soluble vascular endothelial growth factor receptor‐1 secretion in HUVECs; more importantly, p38 inhibition is capable of conferring protection for HUVECs under H/R exposure via suppression of OS and cell apoptosis . Consistently with our results, NCAM1 inhibition would be cardioprotective, which enables to reduce heart failure severity and counteract the deleterious pathological controlling of tumor growth factor‐β1 in a p38‐dependent pathway …”

“…39 Consistently with our results, NCAM1 inhibition would be cardioprotective, which enables to reduce heart failure severity and counteract the deleterious pathological controlling of tumor growth factor-β1 in a p38-dependent pathway. 40 In addition, it has been found in our study that NCAM1 gene silencing strengthens the HUVEC migration and invasion abilities after H/R treatment. NCAM1 knockdown could decrease the neural invasion and paralysis.…”

Tumorigenic proteins upregulated in the MYCN-amplified IMR-32 human neuroblastoma cells promote proliferation and migration

“…Of note, various studies have recently implicated L1-CAM in cancer stem-cell maintenance and propagation ( 37 ), the activation of DNA damage checkpoint response that confers resistant to radiation therapy ( 38 ) and cancer cell migration and malignancy ( 39 ) in glioblastoma and neuroblastoma ( 40 ). Moreover, the strong interactions between L1-CAM and EGFR , RANBP9 and NCAM1 (which affiliates with TGF-β ) ( 41 ) and NRP1 ( Fig. 3 ), may enhance IMR-32 cell invasion and metastasis via an angiogenesis-driven, migratory mechanism.…”

Patient mutations linked to arrhythmogenic cardiomyopathy enhance calpain-mediated desmoplakin degradation

“…Immunofluorescence was performed on paraffin-embedded nonfailing donor hearts and biopsies from individual III-26 using standard protocols (41,42). Prepared sections were imaged at a magnification of ×40 with a Zeiss 780 confocal fluorescent microscope.…”