Blockade of endogenous angiotensin II type I receptor agonistic autoantibody activity improves mitochondrial reactive oxygen species and hypertension in a rat model of preeclampsia

Abstract

Preeclampsia (PE) is characterized by new-onset hypertension that usually occurs in the third trimester of pregnancy and is associated with oxidative stress and angiotensin II type 1 receptor agonistic autoantibodies (AT1-AAs). Inhibition of the AT1-AAs in the reduced uterine perfusion pressure (RUPP) rat, a model of PE, attenuates hypertension and many other characteristics of PE. We have previously shown that mitochondrial oxidative stress (mtROS) is a newly described PE characteristic exhibited by the RUPP rat that contributes to hypertension. However, the factors that cause mtROS in PE or RUPP are unknown. Thus, the objective of the current study is to use pharmacologic inhibition of AT1-AAs to examine their role in mtROS in the RUPP rat model of PE. AT1-AA inhibition in RUPP rats was achieved by administration of an epitope-binding peptide (′n7AAc′). Female Sprague-Dawley rats were divided into the following two groups: RUPP and RUPP + AT1-AA inhibition (RUPP + ′n7AAc′). On day 14 of gestation (GD), RUPP surgery was performed; ′n7AAc′ peptide (2 µg/μL) was administered by miniosmotic pumps in a subset of RUPP rats; and on GD19, sera, placentas, and kidneys were collected. mitochondrial respiration and mtROS were measured in isolated mitochondria using the Oxygraph 2K and fluorescent microplate reader, respectively. Placental and renal mitochondrial respiration and mtROS were improved in RUPP + ′n7AAc′ rats compared with RUPP controls. Moreover, endothelial cells (human umbilical vein endothelial cells) treated with RUPP + ′n7AAc′ sera exhibited less mtROS compared with those treated with RUPP sera. Overall, our findings suggest that AT1-AA signaling is one stimulus of mtROS during PE.

Oxidative Stress: A Unifying Paradigm in Hypertension

“…Oxidative stress has been causally linked to increased blood pressure in various experimental models of hypertension, including genetic hypertension (spontaneously hypertensive rats [SHRs], stroke-prone SHRs [SHR-SPs]), endocrineinduced hypertension [Ang II, aldosterone, deoxycorticosterone acetate (DOCA)]), surgically induced hypertension (2-kidney 1-clip [2K1C], aortic banding), diet-induced hypertension (salt, fat, zinc), neurogenic hypertension, pulmonary hypertension, and preeclampsia. 17,[52][53][54][55][56] Biomarkers of oxidative stress, including plasma and urinary thiobarbituric acidereactive substances (TBARS) and F 2a -isoprostanes, tissue concentrations of O 2 À and H 2 O 2 , and activation of Noxs and xanthine oxidase, are increased, whereas levels of NO and antioxidant enzymes are reduced in experimental hypertension. [52][53][54][55][56][57] Further supporting a role for oxidative stress in the pathophysiology of hypertension are studies demonstrating blood pressureelowering effects of antioxidants, ROS scavengers, and Nox inhibitors.…”

“…17,[52][53][54][55][56] Biomarkers of oxidative stress, including plasma and urinary thiobarbituric acidereactive substances (TBARS) and F 2a -isoprostanes, tissue concentrations of O 2 À and H 2 O 2 , and activation of Noxs and xanthine oxidase, are increased, whereas levels of NO and antioxidant enzymes are reduced in experimental hypertension. [52][53][54][55][56][57] Further supporting a role for oxidative stress in the pathophysiology of hypertension are studies demonstrating blood pressureelowering effects of antioxidants, ROS scavengers, and Nox inhibitors. Treatment with antioxidant vitamins (vitamins C and E), SOD mimetics (tempol [4-hydroxy-2,2,6,6-tetramethyl piperidinoxyl]), free radical scavengers (N-acetyl-L-cysteine), tetrahydrobiopterin, nonspecific Nox inhibitors (apocynin, diphenylene iodinium), and specific Nox inhibitors (gp91dstat, GKT compounds) reduce oxidative stress and ameliorate or prevent development of hypertension and associated target-organ damage.…”

Vascular endothelial mitochondrial oxidative stress in response to preeclampsia: a role for angiotension II type 1 autoantibodies

“…15 We have shown recently that 'n7AAc' decreases blood pressure, vasoactive factors, cytolytic natural killer cells, and mitochondrial oxidative stress, thereby providing an improved outcome in response to placental ischemia in the pregnant RUPP rat model of PE. 16 Although 'n7AAc' improved the outcomes in animal models of PE, it is unknown if it could improve factors associated with PE in patients.…”

“…26 Moreover, we have recently reported a role for AT1-AAs in mitochondrial dysfunction and hypertension in response to placental ischemia. 16 Thus, the objective of the current study was to determine if circulating factors, such as the AT1-AAs, from the PE patients impair vascular endothelial cell mitochondrial function, indicated by mitochondrial oxidative stress and impaired respiration, and if this could be attenuated with 'n7AAc' .…”

Oxidative Stress and Its Association with COVID-19: A Narrative Review

“…Oxidative stress results in the impairment of the endothelial function and development of cardiovascular diseases through distorting the balance between high reactive oxygen species (ROS) and low NO production in particular superoxide [22]. OS and hypertension are associated in various ways including hypertension induced by endocrine (aldosterone, AT II, deoxycorticosterone acetate DOCA)), stroke-prone SHR (SHRSP), genetic hypertension (spontaneously hypertensive rats (SHR), diet-induced hypertension (zinc, fat, salt), hypertension induced by surgery (two-kidney one clip (2K1C), aortic banding), pre-eclampsia, neurogenic hypertension and pulmonary hypertension [77], [78], [79]. Vascular injuries as a result of endothelial dysfunctions are linked to high-production levels of vascular ROS, OS, and vascular inflammations [80].…”