The role of human cytomegalovirus in atherosclerosis: a systematic review

Abstract

Atherosclerosis is a progressive vascular disease with increasing morbidity and mortality year by year in modern society. Human cytomegalovirus (HCMV) infection is closely associated with the development of atherosclerosis. HCMV infection may accelerate graft atherosclerosis and the development of transplant vasculopathy in organ transplantation. However, our current understanding of HCMV-associated atherosclerosis remains limited and is mainly based on clinical observations. The underlying mechanism of the involvement of HCMV infection in atherogenesis remains unclear. Here, we summarized current knowledge regarding the multiple influences of HCMV on a diverse range of infected cells, including vascular endothelial cells, vascular smooth muscle cells, monocytes, macrophages, and T cells. In addition, we described potential HCMV-induced molecular mechanisms, such as oxidative stress, endoplasmic reticulum stress, autophagy, lipid metabolism, and miRNA regulation, which are involved in the development of HCMV-associated atherogenesis. Gaining an improved understanding of these mechanisms will facilitate the development of novel and effective therapeutic strategies for the treatment of HCMV-related cardiovascular disease.

Genetic Predisposition of Anti-Cytomegalovirus Immunoglobulin G Levels and the Risk of 9 Cardiovascular Diseases

“…CMV infection enables a lifetime latent phase with capacities of infecting cells, generally epithelial cells and peripheral blood mononuclear cells, and reactivation with higher titers of IgG. Interestingly, CMV also affects vessel wall cells, with its infection linked to coronary heart disease and atherosclerosis (Wang et al, 2017;Zhu and Liu, 2020), which was also consistent with the conclusions of our study, revealing a causal association between genetic predisposition of anticytomegalovirus IgG levels and higher risk of coronary artery disease. Notably, our study first establishes the causative correlation for CMV IgG level in peripheral artery disease, a disease that mainly shares similar mechanisms of atherosclerosis with coronary artery disease but involves peripheral vessel beds, in line with a population-based case-control study (Bloemenkamp et al, 2002) previously observing a positive correlation in women between CMV IgG titer and peripheral artery disease (OR = 1.6, 95% CI, 1.1-2.3).…”

The Role of CMV Infection in Primary Lesions, Development and Clinical Expression of Atherosclerosis

“…Reactivation of the latent CMV infection in endothelial cells recruits macrophages and neutrophils by secreting chemoattractant and adhesion factors (MCP-1, VCAM-1, ICAM-1, and CXC), promoting internalization of oxLDL and foamy cells formation. CMV seems to upregulate several important proatherogenic molecules responsible for LDL and VLDL cellular uptake and cholesterol synthesis (NPC1L1, HMGCS1, HMGCR, LRP10, 11, 12, and SCARB) and downregulates anti-atherogenic proteins (ApoA1, ApoM, and ApoH) [50]. CMV-infected endothelial cells inhibit angiogenesis and promote abnormal vessel formation, a very important phenomenon already demonstrated in congenital CMV infection [51][52][53].…”

Vitamin D3 Suppresses Human Cytomegalovirus-Induced Vascular Endothelial Apoptosis via Rectification of Paradoxical m6A Modification of Mitochondrial Calcium Uniporter mRNA, Which Is Regulated by METTL3 and YTHDF3

“…Growing evidence indicates that HCMV infection may be the initiating factor of atherosclerosis and that it plays important roles in the occurrence and development of atherosclerosis ( Hsich et al, 2001 ; Jia et al, 2017 ; Zhu and Liu, 2020 ). In the process of HCMV-induced atherosclerosis, the dysfunction and even apoptosis of vascular endothelial cells are the distinctive features ( Shen et al, 2004 ; Utama et al, 2006 ).…”