Original ArticleRole of atrial endothelial cells in the development of atrial fibrosis and fibrillation in response to pressure overload
Introduction
Leukocyte adhesion to the endothelium is a first step in atherosclerosis progression. Leukocyte migration into the intima is mediated via monocyte chemoattractant protein-1 (MCP-1), a key chemokine that recruits monocytes to atherosclerotic lesions [1], [2]. Endothelial function is impaired by oxidized low-density lipoprotein and the turbulent blood flow in arterial branching areas, which increases endothelial cell expression of adhesion molecules, such as E-selectin, intercellular adhesion molecule (ICAM-1), and vascular cell adhesion molecule (VCAM-1) [3]. Hence, endothelium works as a key moderator in the progression of atherosclerosis.
Increasing evidence indicates that left atrial (LA) inflammation and interstitial fibrosis contribute to the pathogenesis of atrial fibrillation (AF) [4], [5]. We previously reported that LA fibrosis and AF vulnerability were increased 28 days after suprarenal abdominal aortic constriction (AAC) in rats [6]. Similar to the progression of atherosclerosis, MCP-1, ICAM-1, VCAM-1, and E-selectin expressions were significantly increased and macrophages were recruited across the atrial endocardium in AF patients [7], [8], [9]. These results may indicate the possible pathologic similarity between AF and atherosclerosis, and dysfunction of the endothelium may be a critical facilitator in both pathogenesis. Chronic exposure to pressure overload overwhelms the defense mechanisms of endothelial cells and compromises its functional integrity. Endothelial dysfunction exhibits proinflammatory, pro-oxidant, proliferative, and proadhesion features, which will facilitate AF substrate formation [10]. Several studies have suggested that inflammation exerts its remodeling effects through reactive oxygen species (ROS) [11]. ROS can activate matrix metalloproteinases, resulting in an imbalance between accumulation and breakdown of extracellular matrix, enhancing LA fibrosis [12]. In fact, inflammatory cells have been demonstrated to infiltrate atrial tissue [13]. In the present study, we investigated the early morphological changes in the atrial endothelium in response to pressure overload and whether the changes in endothelium may induce inflammation and fibrosis in the LA which may lead to AF.
Section snippets
Materials and methods
All experimental procedures were conducted in accordance with the guidelines of the Physiological Society of Oita University for the care and use of laboratory animals, which follow the guidelines established by the US National Institutes of Health.
Physiological changes induced by AAC
The physiological and hemodynamic characteristics are summarized in Table 2. The LV systolic blood pressure, heart weight, and heart-to-body weight ratio measured on the third day after the procedure were significantly increased in the AAC rats (n=20) compared with those in the sham-operated rats (n=20). The echocardiographic findings are summarized in Table 3 (n=10 for each group). Pressure overload resulted in a significant increase in interventricular septum wall thickness and LV posterior
Discussion
The core findings of the present study are as follows: (a) the LA endothelium exhibited morphological changes shortly after the AAC procedure: LA was significantly dilated, and LA endothelial cells were hypertrophied with small gaps along the cell border; (b) AAC increased macrophage infiltration into LA tissue through endothelial gaps; (c) AAC enhanced the expression of MCP-1, E-selectin, ICAM-1, and VCAM-1 in the LA, and MCP-1 and E-selectin were expressed in the LA endothelium; and (d) AAC
Conclusion
In conclusion, the results presented here suggest that LA endothelial cells respond quickly to pressure overload structurally and functionally to express MCP-1 and adhesion molecules. These molecules may be associated with the recruitment of macrophages to endothelial surface and their possible transmigration into the LA subendothelial tissue layer via the endothelial gap. Hence, initial profibrotic process of atrium in response to pressure overload appears quite similar to that of
Acknowledgments
The authors acknowledge the help of the following in carrying out the electron microscopic studies: Hiroaki Kawazato and Aiko Yasuda, Division of Biomolecular Medicine and Medical Imaging, Institute of Scientific Research, Faculty of Medicine, Oita University, Oita, Japan.
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Conflict of interest: none.