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Dysregulated ACE/Ang II And ACE2/Ang 1‐7 Signalling Provokes Cardiovascular and Neuroinflammatory Outcomes of Endotoxemia in Weaning Preeclamptic Rats
Author(s) -
Abuiessa Salwa,
Helmy Mai,
ElGowilly Sahar,
ElMas Mahmoud
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.00370
Subject(s) - losartan , medicine , endocrinology , pioglitazone , angiotensin ii , rostral ventrolateral medulla , apelin , angiotensin ii receptor type 1 , aliskiren , renin–angiotensin system , blood pressure , receptor , heart rate , type 2 diabetes , diabetes mellitus
Weaning preeclamptic (PE) rats exhibit exaggerated endotoxic signs of hypotension and cardiac autonomic neuropathy. Considering the role of renin‐angiotensin system (RAS) in maternal programming during PE, we investigated the hypothesis that gestational modulation of offensive (Ang II) and defensive (Ang 1‐7) components of RAS alleviates cardiovascular hyperresponsiveness of weaning PE mothers to postpartum endotoxemia. PE was induced by treating pregnant rats with L‐NAME for 7 days starting from gestational day 14. The PE‐associated elevations in gestational blood pressure and proteinuria were reduced after gestational treatment with Ang 1‐7 (Ang II‐derived vasodilator), losartan (AT1 receptor antagonist), pioglitazone (RAS modulator), or combined losartan/pioglitazone, with the latter being the most effective. In weaning PE rats, the hypotension and enhanced spectral index of cardiac parasympathetic dominance caused by i.v. lipopolysaccharides (LPS, 5 mg/kg) were attenuated by all therapies; Ang 1‐7 was the least effective in reducing LPS hypotension. Pioglitazone and Ang 1‐7 were more effective in reversing increases and decreases in left ventricular contractility and isovolumic relaxation time constant, respectively, seen in endotoxic PE mothers. Immunohistochemically, cardiac, but not brainstem rostral ventrolateral medulla (RVLM), TLR‐4 expression was increased in endotoxic PE rats and this effect was abrogated by Ang 1‐7 or losartan/pioglitazone. The same treatments blunted the increased cardiac ACE expression, whereas only losartan/pioglitazone lowered the upregulated RVLM ACE expression. ACE2 expression was decreased in RVLM, but not heart, and this was preferentially reversed by Ang 1‐7. Overall, the rectification of ACE/Ang II and ACE2/Ang 1‐7 imbalances alleviates sensitized cardiovascular and inflammatory actions of endotoxemia in weaning PE mothers.