Loss of CEACAM1, a Tumor-Associated Factor, Attenuates Post-infarction Cardiac Remodeling by Inhibiting Apoptosis.

Yan Wang,Nvqin He,Guojun Chen,Xinzhong Li,Yi Yan,Jianping Bin,Wangjun Liao,Yulin Liao,Gangbin Chen,Shuxin Shen,Chuanxi Zhang,Yanmei Chen

doi:10.1038/srep21972

Abstract

Carcinoembryonic antigen-related cell adhesion molecule1 (CEACAM1) is a tumor-associated factor that is known to be involved in apoptosis, but the role of CEACAM1 in cardiovascular disease is unclear. We aims to investigate whether CEACAM1 influences cardiac remodeling in mice with myocardial infarction (MI) and hypoxia-induced cardiomyocyte injury. Both serum in patients and myocardial CEACAM1 levels in mice were significantly increased in response to MI, while levels were elevated in neonatal rat cardiomyocytes (NRCs) exposed to hypoxia. Eight weeks after MI, a lower mortality rate, improved cardiac function, and less cardiac remodeling in CEACAM1 knock-out (KO) mice than in their wild-type (WT) littermates were observed. Moreover, myocardial expression of mitochondrial Bax, cytosolic cytochrome C, and cleaved caspase-3 was significantly lower in CEACAM1 KO mice than in WT mice. In cultured NRCs exposed to hypoxia, recombinant human CEACAM1 (rhCEACAM1) reduced mitochondrial membrane potential, upregulated mitochondrial Bax, increased cytosolic cytochrome C and cleaved caspase-3, and consequently increased apoptosis. RhCEACAM1 also increased the levels of GRP78 and CHOP in NRCs with hypoxia. All of these effects were abolished by silencing CEACAM1. Our study indicates that CEACAM1 exacerbates hypoxic cardiomyocyte injury and post-infarction cardiac remodeling by enhancing cardiomyocyte mitochondrial dysfunction and endoplasmic reticulum stress-induced apoptosis.

Highlights

There is growing evidence of direct links between cancer and cardiovascular disease[1]
In mice with myocardial infarction (MI), myocardial Carcinoembryonic antigen-related cell adhesion molecule1 (CEACAM1) mRNA in the infarct zone started to up-regulate at 6 h, reached the peak at 12 h (Fig. 2A), while in the non-infarct zone it was started to up-regulate at 24 h after MI (Fig. 2A)
Expression of CEACAM1 was significantly increased in cultured neonatal rat cardiomyocytes (NRCs) exposed to hypoxia (Fig. 2E) but not in cardiac fibroblasts (Supplementary Figure S1B), and CEACAM1 localized on the cell membrane and parts of the cytosol of cardiomyocytes as detected by immunofluorescence

Summary

Introduction

There is growing evidence of direct links between cancer and cardiovascular disease[1]. Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1, termed CD66a) is a transmembrane protein that has been recognized as an important tumor-associated factor which suppresses or promotes carcinogenesis in a context-dependent manner[13,14], but it remains unknown whether CEACAM1 has any role like p53 in cardiovascular disease It was originally identified as a tumor-associated gene[15,16,17], CEACAM1 has been found to promote apoptosis of various cells such as pulmonary and mammary epithelial cells[18,19], oral keratinocytes[20], cancer cells and Jurkat T cells[21,22]. To explore the potential mechanisms, the influence of loss and gain of CEACAM1 function on mitochondrial activity, ER stress and apoptosis were investigated in cultured cardiomyocytes exposed to hypoxia

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