Co‐localization of angiotensin‐converting enzyme 2‐, octomer‐4‐ and CD34‐positive cells in rabbit atherosclerotic plaques

Abstract

Angiotensin-converting enzyme 2 (ACE2) is a novel enzyme with possible implications in the treatment of blood pressure disorders. Recent evidence suggests that an upregulation of ACE2 can be stimulated by all-trans retinoic acid (at-RA); however, at-RA also affects regulation of the stem-cell marker octomer-4 (Oct-4) and thus cellular differentiation. We have previously shown that smooth muscle cells and macrophages present within rabbit atherosclerotic plaques are positive for ACE2, Oct-4 and the haematopoietic stem-cell marker CD34. Thus, to provide evidence that possible at-RA treatment could affect both plaque cellular biology (via effects on cellular differentiation) and blood pressure (via ACE2), it is vital to show that cells with atherosclerotic plaques co-express all three markers. Thus, we sought to provide evidence that a subset of cells within atherosclerotic plaques is positive for ACE2, Oct-4 and CD34. We used New Zealand White rabbits that were fed a control diet supplemented with 0.5% cholesterol plus 1% methionine for 4 weeks and then allowed to consume a normal diet for 10 weeks. Immunohistochemistry was performed by standard techniques. We report that ACE2, Oct-4 and CD34 were all present within atherosclerotic plaques. Although macrophages were positive for all three markers, spindle-shaped cells in the media did not show all three markers. The endothelium overlying normal arterial wall showed positive Oct-4 and ACE2 immunoreactivity, but CD34 immunoreactivity was patchy, indicating that such cells might not have fully differentiated. It is concluded that cells in atherosclerotic plaques express co-express ACE2, Oct-4 and CD34. Further studies aimed at establishing the effects of all-trans retinoic acid on blood pressure and atherosclerotic cell differentiation are warranted.

Association of all-trans retinoic acid treatment with the renin-angiotensin aldosterone system expression in glomerulosclerosis rats

“…24 In this study, we found that ATRA could up-regulate the expression of ACE2 and could inhibit the expression of angiotensin I, ACE1 and angiotensin II. Zulli et al 25 found that ATRA could stimulate ACE2 expression in rabbit atherosclerotic plaques. Zhong et al 24 found that chronic ATRA treatment increased the gene and protein expression of ACE2, resulting in the reduction of blood pressure and the attenuation of myocardial damage in spontaneously hypertensive rats.…”

Angiotensin converting enzyme 2 and atherosclerosis

“…Studies on its cellular distribution in atherosclerosis show that ACE2 is expressed in endothelial cells (ECs) [34,35], vascular smooth muscle cells (VSMCs) [29,34] and macrophages [29,34,35]. Gene over-expression studies show that overexpression of ACE2 by gene transfer can attenuate the progression of atherosclerotic lesions when the ACE2 gene is transferred four weeks after injury in a rabbit model of atherosclerosis [29].…”

“…ACE2 is expressed in atherosclerosis in experimental animals [29,34,35]. Studies on its cellular distribution in atherosclerosis show that ACE2 is expressed in endothelial cells (ECs) [34,35], vascular smooth muscle cells (VSMCs) [29,34] and macrophages [29,34,35].…”

Pharmacologic modulation of ACE2 expression

“…Also, at-RA affects regulation of the stem cell marker octomer-4 (Oct-4) and eventually, cellular differentiation. Zulli et al [ 27 ] showed that cells within atherosclerotic plaques of New Zealand White rabbits co-express ACE2 and the hematopoietic stem cell marker, CD34. Thus, at-RA treatment could affect plaque cellular biology via effects on cellular differentiation and blood pressure via its effect on ACE2 [ 27 ].…”