ET _A Receptor Mediates Altered Leukocyte-Endothelial Cell Interaction and Adhesion Molecules Expression in DOCA–Salt Rats

Abstract

Abstract-Leukocyte adhesion to endothelial cells plays a key role in inflammatory processes associated with end-organ injury. Endothelin-1 (ET-1), which stimulates inflammatory processes, contributes to cardiovascular damage in deoxycorticosterone (DOCA)-salt hypertension. We investigated whether ET A receptor blockade modulates in vivo leukocyte-endothelial cell interactions and expression of cell adhesion molecules (CAM) involved in these processes. DOCA-salt and control uninephrectomized rats were treated with the ET A antagonist BMS182874 (40 mg/kg per day) or vehicle. Analysis of CAMs expression by reverse transcription-polymerase chain reaction and immunohistochemistry showed increased cardiac platelet selectin (P-selectin), detected mainly in endothelial cells, and vascular cell adhesion molecule-1 (VCAM-1), but not intercellular adhesion molecule-1 (ICAM-1), in DOCA-salt rats. Cardiac expression of endothelial selectin (E-selectin) was decreased, whereas immunoreactivity to ED-1 and myeloperoxidase (MPO) activity, markers of macrophage and leukocyte infiltration, respectively, were increased in DOCA-salt. Leukocyte-endothelial cell interaction, functionally assessed in venules of internal spermatic fascia by intravital microscopy, was significantly altered in DOCA-salt rats as evidenced by increased leukocyte adhesion and decreased rolling. BMS182874 treatment normalized leukocyte-endothelium interactions, decreased cardiac VCAM-1 expression in DOCA and control groups, and had no effects on ICAM-1 expression. BMS182874 also increased E-selectin and abolished P-selectin expression in DOCA-salt, but not in control rats. The ET A antagonist reduced cardiac ED-1 content and MPO activity and prevented cardiac damage in DOCA-salt rats. These data indicate that ET-1 participates, via activation of ET A receptors, in altered leukocyte-endothelial cell interactions in DOCA-salt rats, possibly by modulating expression of CAMs, and that the inflammatory status is associated with cardiac damage in mineralocorticoid hypertension.

Depletion of endogenous kallistatin exacerbates renal and cardiovascular oxidative stress, inflammation, and organ remodeling

“…DOCA-salt hypertensive rats exhibit renal inflammation in association with increased oxidative stress, whereas treatment with anti-oxidants was shown to decrease blood pressure, aortic superoxide formation, and renal monocyte/macrophage accumulation (3). Furthermore, macrophage infiltration and expression of cell adhesion molecules are increased in the hearts of DOCA-salt rats (1,6). In our study, anti-KS antibody administration caused a dramatic increase in monocyte/macrophage accumulation as well as TNF-␣ and ICAM-1 expression in both the kidney and heart.…”

Cardiomyocyte Mineralocorticoid Receptors Are Essential for Deoxycorticosterone/Salt-Mediated Inflammation and Cardiac Fibrosis

“…5 Our data suggest that cardiomyocyte MR signaling may also regulate cell adhesion factor intercellular adhesion molecule-1 at baseline, but not in response to DOC/salt treatment as suggested previously. 11,19 Although macrophage recruitment is maintained in MyoMRKO mice, oxidative stress (NOX2 and p22phox) and inflammatory markers (CCR5) are substantially lower than for WT mice, suggesting that the tissue response to the DOC/salt stress is already limited at this early stage.…”

Deoxycorticosterone Acetate/Salt–Induced Cardiac But Not Renal Injury Is Mediated By Endothelial Mineralocorticoid Receptors Independently From Blood Pressure

“…DOCA/salt increased the expression of vascular cell adhesion molecule Vcam1 in wild-type endothelial cells, which was fully prevented by MR deletion. Aldosterone or DOCA treatment has been associated with an increased expression of adhesion molecules in the heart 5,45,46 previously. We now demonstrate that is directly mediated via MR in endothelial cells.…”