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Background and Purpose: Previous studies demonstrated that intraplaque haemorrhage increased the contents of cholesterol and oxidants in atherosclerotic plaques. The present study was aimed to test the hypothesis that enhanced expression of haem oxygenase-1 (HO-1) may stabilize vulnerable plaques., Experimental Approach: Intravascular ultrasound (IVUS) was performed to identify three similar abdominal aortic plaques in each of 58 fat-fed New Zealand rabbits after aortic balloon injury. With the guidance of IVUS, 50 microL autologous erythrocytes (RBC) or normal saline (NS) were injected from adventitia into two of the pre-selected plaques, respectively, whereas the third plaque served as a blank control. All rabbits were randomly divided into two groups, receiving intraperitoneal injection of haemin and saline respectively., Key Results: Compared with NS or control plaques, RBC plaques had more macrophage infiltration and lipid content, thinner plaque fibrous cap, and higher expression of inflammatory factors and incidence of plaque rupture. RBC plaques in the haemin group had about a 50% lower incidence of plaque rupture than those in the control group., Conclusions and Implications: Haem oxygenase-1 may eliminate haem or other oxidants, exert unexpected anti-oxidative and anti-inflammatory effects and serve as a promising approach to the direct inhibition of erythrocyte-induced plaque instability.

Erythrocytes are considered a new culprit contributing to atherosclerosis. Plaques with intraplaque hemorrhage are prone to new plaque hemorrhage, which may not only stimulate the progression of atherosclerosis but also promote the transition from a stable to an unstable lesion. However, the role of erythrocytes in inducing the vulnerability of plaque with intraplaque hemorrhage and the possible mechanism involved are not well understood. Recently, increased cholesterol level from erythrocytes was reported to expand the lipid core of plaque. As well, heme, iron and phospholipids derived from erythrocytes trigger peroxidization in vitro, which is strongly associated with the progression of atherosclerosis. We speculate that erythrocytes trapped in plaque may induce vulnerability of atherosclerotic plaques not only by accumulating lipids but also by promoting peroxidization within plaques, thereby expanding the lipid core, increasing the infiltration of inflammatory cells and attenuating the fibrous cap of plaques. This proposition may provide clues into the development of novel treatments to increase the stability of atherosclerotic plaques.

To test our hypothesis that erythrocytes may induce plaque vulnerability and investigate the mechanism involved, we established a novel model of intraplaque hemorrhage in 56 New Zealand white rabbits with established plaques. Three distinct abdominal aortic plaques with similar thickness were identified in each rabbit with use of intravascular ultrasound (IVUS) imaging. Rabbits were equally divided into 4 groups depending on dosage of treatment; with the guidance of IVUS, one of the three plaques from each rabbit was injected from adventitia with autologous erythrocytes (RBC) or cholesterol (CH) for the following groups: RBC, 50 microL or 100 microL, and CH, 50 microL or 100 microL. One of the other two plaques in each rabbit received an equal volume of normal saline (NS) and one received no injection. Plaques in the 100 microL RBC group had a higher plaque rupture rate than its respective NS or blank controls plaques (57.1% vs. 14.3% or 14.3%, P<0.05). Plaques from the RBC or cholesterol groups showed, dose-dependently, more macrophage infiltration, more superoxide and lipid content, thinner plaque fibrous cap, higher mRNA level of MCP-1, IL-1 or IFN-gamma and higher vulnerability index than controls, especially in the RBC group. Thus, erythrocyte treatment can dose-dependently induce the vulnerability of plaques. Accumulation of lipid content and augmentation of oxidative stress and inflammation in the plaques are the probable pathological mechanisms involved.

Cardiovascular disease (CVD) is a leading cause of mortality worldwide. Atherosclerosis, a multifactorial disease with complicated pathogenesis, is the main cause of CVD, underlying several major adverse cardiovascular events. Obesity is the main cause of obstructive sleep apnea (OSA) and a significant risk for atherosclerosis. OSA is an independent risk factor for CVD. Recent research has focused on understanding the underlying molecular mechanisms by which OSA influences atherosclerosis pathogenesis. The role of exosomes in this process has attracted considerable attention. Exosomes are a type of extracellular vesicles (EV) that are released from many cells (both healthy and diseased) and mediate cell-to-cell communication by transporting microRNAs (miRNAs), proteins, mRNAs, DNA, or lipids to target cells, thereby modulating the functions of target cells and tissues. Intermittent hypoxia in OSA alters the exosomal carrier in circulation and promotes the permeability and dysfunction of endothelial cells, which have been associated with the pathogenesis of atherosclerosis. This review discusses the potential roles of exosomes and exosome-derived molecules in the development and progression of OSA-related atherosclerosis. Additionally, we explore the possible mechanisms underlying OSA-related atherosclerosis and provide new insights for the development of novel exosome-based therapeutics for OSA-related atherosclerosis and CVD. [ABSTRACT FROM AUTHOR]