Cardiotrophin-1 Deficiency Abrogates Atherosclerosis Progression

Kapka Miteva,François Mach,Karim J Brandt,Fabienne Burger,Rodrigo A Fraga-Silva,Aline Roth,Mohamed Asrih,Fabrizio Montecucco,Nikolaos Stergiopulos,Daniela Baptista

doi:10.1038/s41598-020-62596-6

Abstract

Cardiotrophin-1 (CT-1) is associated with cardiovascular (CV) diseases. We investigated the effect of CT-1 deficiency in the development and progression of atherosclerosis in double knockout Apoe−/−ct-1−/− mice. Apoe−/− C57Bl/6 or Apoe−/−ct-1−/− C57Bl/6 mice were fed a normal chow diet (NCD) or a high-cholesterol diet (HCD). After sacrifice, serum triglycerides, total cholesterol, low-density lipoprotein cholesterol (LDL-C), free fatty acids and systemic paracrine factors were measured. Intraplaque lipid and collagen content were quantified in the aortic sections. Immune cell populations in spleen, lymph nodes and aorta were analysis by flow cytometry. Apoe−/−ct-1−/− mice in accelerated atherosclerosis exhibited a reduction of total cholesterol, LDL-C, atherosclerotic plaques size in the aortic root and in the abdominal aorta and improved plaque stability in comparison to Apoe−/− mice. CT-1 deficiency in Apoe−/− mice on (HCD) promoted atheroprotective immune cell responses, as demonstrated by a rise in plasma anti-inflammatory immune cell populations (regulatory T cells, Tregs; regulatory B cells, Bregs and B1a cells) and atheroprotective IgM antibodies. CT-1 deficiency in advanced atherosclerosis mediated regulation of paracrine factors, such as interleukin (IL)-3, IL-6, IL-9, IL-15, IL-27, CXCL5, MCP-3, MIP-1α and MIP-1β. In a model of advanced atherosclerosis, CT-1 deficiency induced anti-inflammatory and atheroprotective effects which resulted in abrogation of atheroprogression.

Highlights

Cardiovascular (CV) diseases are the leading cause of death and morbidity in developed countries[1]
highcholesterol diet (HCD) significantly increased the levels of total cholesterol, low-density lipoprotein (LDL) and low-density lipoprotein cholesterol (LDL-C) in Apoe−/− mice (Fig. 1)
LDL levels are a causal factor in atherosclerosis, the effect of CT-1 deficiency on LDL levels in accelerated atherosclerosis is an important prerequisite for the improvement of cardiovascular outcomes

Summary

Introduction

Cardiovascular (CV) diseases are the leading cause of death and morbidity in developed countries[1]. The fibrous cap is an atheroprotective layer of vascular smooth muscle cells (VSMCs) that covers the atherosclerotic plaque[2] and induces acute thrombo-occlusive events, such as myocardial infarction and stroke[3]. CT-1 binds to glycoprotein 130 (gp130) and leukemia inhibitory factor receptor (LIFR)[4] and induces cardiac protection via inhibition of apoptosis, suggesting a protective role of CT-1 in response to acute hypoxia in vivo[19] which is in line with other studies showing the anti-apoptotic effect of CT-1 treatment on embryonic, neonatal, and adult cardiomyocytes[6,20,21]. On the other hand CT-1 has been shown promotes cardiac hypertrophy[22], atherosclerosis, arterial stiffness[23] and vascular inflammation[5]. We evaluated the impact of CT-1 deficiency on atherosclerotic lesion size, plaque stability, cholesterol levels and inflammation

Methods

Results

Conclusion