Ovariectomy provokes inflammatory and cardiovascular effects of endotoxemia in rats: Dissimilar benefits of hormonal supplements

El-Lakany, Mohammed A.; Fouda, Mohamed A.; El‐Gowelli, Hanan M.; El‐Mas, Mahmoud M.

doi:10.1016/j.taap.2020.114928

Cited by 11 publications

(6 citation statements)

References 57 publications

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“…The lack of such effect in the female offspring is consistent with previous clinical 44 , 45 and experimental studies 3 , 38 , 46 , which suggested a protective role for female sex hormones against endotoxic cardiovascular insults. The latter view is reinforced by the the findings that bilateral ovariectomy 47 or pharmacologic blockade of gonadal hormone receptors 12 , 13 uncover clear hypotensive and inflammatory responses to endotoxemia. Notably, the tail‐cuff technique employed in the current study for SBP measurement is believed to suffers some inherent limitations such as the need for preheating and restraining of the animal, which may undermine the reliability of the results 48 .…”

Section: Discussionmentioning

confidence: 99%

The renin-angiotensin system modulates endotoxic postconditioning of exacerbated renal vasoconstriction in preeclamptic offspring

Morgaan

Sallam

El‐Gowelli

et al. 2023

Sci Rep

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We recently reported exacerbated endotoxic signs of neuroinflammation and autonomic defects in offspring of preeclamptic (PE) dams. Here, we investigated whether PE programming similarly modifies hemodynamic and renal vasoconstrictor responsiveness to endotoxemia in PE offspring and whether this interaction is modulated by gestational angiotensin 1–7 (Ang1-7). Preeclampsia was induced by gestational treatment with L-NAME. Adult offspring was challenged with lipopolysaccharides (LPS, 5 mg/kg) and systolic blood pressure (SBP) and renal vasoconstrictions were assessed 4 h later. Male, but not female, offspring of PE rats exhibited SBP elevations that were blunted by LPS. Renal vasoconstrictions induced by angiotensin II (Ang II), but not phenylephrine, were intensified in perfused kidneys of either sex. LPS blunted the heightened Ang II responses in male, but not female, kidneys. While renal expressions of AT1-receptors and angiotensin converting enzyme (ACE) were increased in PE offspring of both sexes, ACE2 was upregulated in female offspring only. These molecular effects were diminished by LPS in male offspring. Gestational Ang1-7 caused sex-unrelated attenuation of phenylephrine vasoconstrictions and preferentially downregulated Ang II responses and AT1-receptor and nuclear factor-kB (NFkB) expressions in females. Together, endotoxemia and Ang1-7 offset in sexually-related manners imbalances in renal vasoconstriction and AT1/ACE/ACE2 signaling in PE offspring.

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Section: Discussionmentioning

confidence: 99%

The renin-angiotensin system modulates endotoxic postconditioning of exacerbated renal vasoconstriction in preeclamptic offspring

Morgaan

Sallam

El‐Gowelli

et al. 2023

Sci Rep

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“…Gonadal hormones have crucial roles in the inflammatory responses ( El-Lakany et al, 2018 ; El-Lakany et al, 2020 ). Estrogen (E 2 ), the main female sex hormone, acts via genomic and non-genomic mechanisms to inhibit inflammatory cascades ( Murphy et al, 2010 ).…”

Section: Introductionmentioning

confidence: 99%

Protein Kinases Mediate Anti-Inflammatory Effects of Cannabidiol and Estradiol Against High Glucose in Cardiac Sodium Channels

Fouda

Ruben

2021

Front. Pharmacol.

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Background: Cardiovascular anomalies are predisposing factors for diabetes-induced morbidity and mortality. Recently, we showed that high glucose induces changes in the biophysical properties of the cardiac voltage-gated sodium channel (Nav1.5) that could be strongly correlated to diabetes-induced arrhythmia. However, the mechanisms underlying hyperglycemia-induced inflammation, and how inflammation provokes cardiac arrhythmia, are not well understood. We hypothesized that inflammation could mediate the high glucose-induced biophyscial changes on Nav1.5 through protein phosphorylation by protein kinases A and C. We also hypothesized that this signaling pathway is, at least partly, involved in the cardiprotective effects of cannabidiol (CBD) and 17β-estradiol (E2).Methods and Results: To test these ideas, we used Chinese hamster ovarian (CHO) cells transiently co-transfected with cDNA encoding human Nav1.5 α-subunit under control, a cocktail of inflammatory mediators or 100 mM glucose conditions (for 24 h). We used electrophysiological experiments and action potential modeling. Inflammatory mediators, similar to 100 mM glucose, right shifted the voltage dependence of conductance and steady-state fast inactivation and increased persistent current leading to computational prolongation of action potential (hyperexcitability) which could result in long QT3 arrhythmia. We also used human iCell cardiomyocytes derived from inducible pluripotent stem cells (iPSC-CMs) as a physiologically relevant system, and they replicated the effects produced by inflammatory mediators observed in CHO cells. In addition, activators of PK-A or PK-C replicated the inflammation-induced gating changes of Nav1.5. Inhibitors of PK-A or PK-C, CBD or E2 mitigated all the potentially deleterious effects provoked by high glucose/inflammation.Conclusion: These findings suggest that PK-A and PK-C may mediate the anti-inflammatory effects of CBD and E2 against high glucose-induced arrhythmia. CBD, via Nav1.5, may be a cardioprotective therapeutic approach in diabetic postmenopausal population.

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“…16 On the other hand, estrogen exhibits anti-inflammatory actions in endotoxic shock and guards against the endotoxemia-evoked alterations in thermoregulatory response, 17 lung damage, 18 and cardiovascular toxicity. 4,19 Despite the established role of androgens in inciting the inflammatory response to endotoxemia, little or no information is currently available concerning whether the modulatory role of male gonadal hormones extends to involve cardiovascular influences of the endotoxic insult. In this study, pharmacologic and molecular studies were undertaken in male rats to address 2 main hypotheses (1) androgens and their biosynthetic pathways are pivotal for triggering the hypotensive and cardiac autonomic depressant effects of endotoxemia, and (2) inflammatory pathways in periphery and/or in brainstem cardiovascular-sensitive nuclei of the NTS and rostral ventrolateral medulla (RVLM) contribute to LPS/androgen interaction.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cardiac and Brainstem Neuroinflammatory Pathways Account for Androgenic Incitement of Cardiovascular and Autonomic Manifestations in Endotoxic Male Rats

Sallam

El‐Gowilly

El‐Mas

2021

Journal of Cardiovascular Pharmacology

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Inconsistent reports are available on the role of testosterone in end-organ damage caused by endotoxemia. Here, pharmacologic, surgical, and molecular studies were employed to assess the testosterone modulation of cardiovascular, autonomic, and peripheral and central inflammatory derangements caused by endotoxemia. Studies were performed in conscious male rats preinstrumented with femoral indwelling catheters for the measurement of blood pressure and subjected to castration or pharmacologic interventions that interrupt the biosynthetic cascade of testosterone. Compared with the effects of lipopolysaccharide (10 mg/kg intravenously) in sham operated rats, 2-week castration reduced the lipopolysaccharide-evoked (1) falls in blood pressure, (2) decreases in time-and frequency-domain indices of heart rate variability, (3) shifts in spectral measures of cardiac sympathovagal balance toward parasympathetic dominance, and (4) increases in protein expressions of toll-like receptor-4 and monocyte chemoattractant protein-1 in heart and medullary neurons of the nucleus tractus solitarius and rostral ventrolateral medulla. While the ameliorating actions of castration on endotoxic cardiovascular manifestations were maintained after testosterone replacement, the concomitant inflammatory signals were restored to near-sham levels. The favorable influences of castration on inflammatory and cardiovascular abnormalities of endotoxemia were replicated in intact rats pretreated with degarelix (gonadotropin-releasing hormone receptor blocker) or finasteride (5a-reductase inhibitor) but not formestane (aromatase inhibitor). The data signifies the importance of androgens and its biosynthetic enzymes in cardiovascular and autonomic insults induced by the endotoxic inflammatory response. Clinically, the interruption of testosterone biosynthesis could offer a potential strategy for endotoxemia management.

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Ovariectomy provokes inflammatory and cardiovascular effects of endotoxemia in rats: Dissimilar benefits of hormonal supplements

Cited by 11 publications

References 57 publications

The renin-angiotensin system modulates endotoxic postconditioning of exacerbated renal vasoconstriction in preeclamptic offspring

The renin-angiotensin system modulates endotoxic postconditioning of exacerbated renal vasoconstriction in preeclamptic offspring

Protein Kinases Mediate Anti-Inflammatory Effects of Cannabidiol and Estradiol Against High Glucose in Cardiac Sodium Channels

Cardiac and Brainstem Neuroinflammatory Pathways Account for Androgenic Incitement of Cardiovascular and Autonomic Manifestations in Endotoxic Male Rats

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