Bazedoxifene-induced vasodilation and inhibition of vasoconstriction is significantly greater than estradiol

Zimmerman, Margaret A.; Hutson, Dillion D.; Mauvais-Jarvis, Franck; Lindsey, Sarah H.

doi:10.1097/gme.0000000000001195

Cited by 9 publications

(4 citation statements)

References 56 publications

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“…In this regard, we have previously demonstrated that BZA induces endothelium‐independent relaxations of rabbit cerebral arteries via, amongst other mechanisms, activation of GPER and ERα . More recently, BZA has also been shown to elicit vasodilation in mice peripheral (mesenteric) arteries to a higher extent than E 2 . Overall, BZA could be included in the list of promising multimodal stroke therapies with a potential to be administered as an adjunctive treatment to mechanical or pharmacological reperfusion.…”

Section: Discussionmentioning

confidence: 96%

The selective oestrogen receptor modulator, bazedoxifene, mimics the neuroprotective effect of 17β‐oestradiol in diabetic ischaemic stroke by modulating oestrogen receptor expression and the MAPK/ERK1/2 signalling pathway

Burguete

Jover‐Mengual

López‐Morales

et al. 2019

J Neuroendocrinology

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Because neuroprotection in stroke should be revisited in the era of recanalisation, the present study analysed the potential neuroprotective effect of the selective oestrogen receptor modulator, bazedoxifene acetate (BZA), in an animal model of diabetic ischaemic stroke that mimics thrombectomy combined with adjuvant administration of a putative neuroprotectant. Four weeks after induction of diabetes (40 mg kg -1 streptozotocin, i.p.), male Wistar rats were subjected to transient middle cerebral artery occlusion (intraluminal thread technique, 60 minutes) and assigned to one of three groups treated with either: vehicle, BZA (3 mg kg -1 day -1 , i.p.) or 17β-oestradiol (E 2 ) (100 μg kg -1 day -1 , i.p.). At 24 hours post-ischaemia-reperfusion, brain damage (neurofunctional score, infarct size and apoptosis), expression of oestrogen receptors (ER)α, ERβ and G protein-coupled oestrogen receptor), and activity of the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK)1/2 and phosphoinositide 3-kinase/Akt pathways were analysed. At 24 hours after the ischaemic insult, both BZA-and E 2 -treated animals showed lower brain damage in terms of improved neurofunctional condition, decreased infarct size and decreased apoptotic cell death.Ischaemia-reperfusion induced a significant decrease in ERα and ERβ expression without affecting that of G protein-coupled oestrogen receptor, whereas BZA and E 2 reversed such a decrease. The ischaemic insult up-regulated the activity of both the MAPK/ERK1/2 and phosphoinositide 3-kinase/Akt pathways; BZA and E 2 attenuated the increased activity of the ERK1/2 pathway, without affecting that of the Akt pathway. The results of the present study lend further support to the consideration of BZA as an effective and safer alternative overcoming the drawbacks of E 2 with respect to improving diabetic ischaemic stroke outcome after successful reperfusion. K E Y W O R D S 17β-oestradiol, apoptosis, bazedoxifene, diabetes, ischaemic stroke, selective oestrogen receptor modulators How to cite this article: Burguete MC, Jover-Mengual T, López-Morales MA, et al. The selective oestrogen receptor modulator, bazedoxifene, mimics the neuroprotective effect of 17β-oestradiol in diabetic ischaemic stroke by modulating oestrogen receptor expression and the MAPK/ERK1/2 signalling pathway. J Neuroendocrinol. 2019;31:e12751.

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Section: Discussionmentioning

confidence: 96%

The selective oestrogen receptor modulator, bazedoxifene, mimics the neuroprotective effect of 17β‐oestradiol in diabetic ischaemic stroke by modulating oestrogen receptor expression and the MAPK/ERK1/2 signalling pathway

Burguete

Jover‐Mengual

López‐Morales

et al. 2019

J Neuroendocrinology

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“…It is obvious that there is strong crosstalk between the CD40/CD40L system and IL6/GP130 in the downstream pathway. Some studies have reported that bazedoxifene may have a protective effect on the cardiovascular system [ 19 ]. Bazedoxifene modulates superoxide production and MCP-1 expression induced by AGE-RAGE in VECs [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

Bazedoxifene Plays a Protective Role against Inflammatory Injury of Endothelial Cells by Targeting CD40

Song

Tang

et al. 2020

Cardiovascular Therapeutics

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The inflammatory response and oxidative stress play key roles in the formation and development of atherosclerosis. Bazedoxifene is a new IL6/GP130 inhibitor recommended by the FDA for clinical use as a selective estrogen receptor modulator. However, its role in cardiovascular diseases has been poorly studied. In our study, we explored the mechanism of bazedoxifene’s protective effect against inflammatory injury of vascular endothelial cells (VECs) stimulated by TNF-α. Various methods were used to verify the effect of bazedoxifene on VECs, including a cell viability assay, a wound healing assay, immunofluorescence staining, and western blotting. Our results showed that TNF-α could induce inflammatory damage to VECs, which manifested as upregulated expression of CD40, increased production of ROS, enhanced adhesion of THP-1 cells to VECs, and impaired viability and migration of VECs, while bazedoxifene could significantly reduce the endothelial damage caused by TNF-α. In addition, we found that an siRNA targeting CD40 dramatically alleviated the VEC damage induced by TNF-α. Therefore, we explored the potential relationship between bazedoxifene and CD40. Our data suggest that bazedoxifene has a protective effect against VEC damage induced by TNF-α and that its underlying mechanism may be related to the regulation of CD40.

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“…Male and female wildtype and global GPER knockout mice were bred and maintained in the institutional vivarium. The presence or absence of GPER was verified using both genotyping and ddPCR as previously described (35). Mice had free access to food and water in a temperature-controlled room (65–75°F) with a 12 h light to dark cycle.…”

Section: Methodsmentioning

confidence: 99%

“…Segments were bathed in Krebs buffer (118 mM NaCl, 25 mM NaHCO 3 , 4.8 mM KCl, 2.5 mM CaCl 2 , 1.2 mM MgSO 4 , 1.2 mM KH 2 PO 4 , and 11 mM glucose; pH 7.4) and mixed with 95% O 2 and 5% CO 2 at 37°C. Normalization and assessment of baseline vascular dynamics were done as previously described (35). Vascular contractility was assessed in response to increasing concentrations of angiotensin II (Ang II; 10 −10 to 10 −6 M) and prostaglandin F2α (PGF2α; 10 −8 to 10 −4 M).…”

Section: Methodsmentioning

confidence: 99%

G Protein-Coupled Estrogen Receptor Protects From Angiotensin II-Induced Increases in Pulse Pressure and Oxidative Stress

et al. 2019

Self Cite

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Our previous work showed that the G protein-coupled estrogen receptor (GPER) is protective in the vasculature and kidneys during angiotensin (Ang) II-dependent hypertension by inhibiting oxidative stress. The goal of the current study was to assess the impact of GPER deletion on sex differences in Ang II-induced hypertension and oxidative stress. Male and female wildtype and GPER knockout mice were implanted with radiotelemetry probes for measurement of baseline blood pressure before infusion of Ang II (700 ng/kg/min) for 2 weeks. Mean arterial pressure was increased to the same extent in all groups, but female wildtype mice were protected from Ang II-induced increases in pulse pressure, aortic wall thickness, and Nox4 mRNA. In vitro studies using vascular smooth muscle cells found that pre-treatment with the GPER agonist G-1 inhibited Ang II-induced ROS and NADP/NADPH. Ang II increased while G-1 decreased Nox4 mRNA and protein. The effects of Ang II were blocked by losartan and Nox4 siRNA, while the effects of G-1 were inhibited by adenylyl cyclase inhibition and mimicked by phosphodiesterase inhibition. We conclude that during conditions of elevated Ang II, GPER via the cAMP pathway suppresses Nox4 transcription to limit ROS production and prevent arterial stiffening. Taken together with our previous work, this study provides insight into how acute estrogen signaling via GPER provides cardiovascular protection during Ang II hypertension and potentially other diseases characterized by increased oxidative stress.

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Bazedoxifene-induced vasodilation and inhibition of vasoconstriction is significantly greater than estradiol

Cited by 9 publications

References 56 publications

The selective oestrogen receptor modulator, bazedoxifene, mimics the neuroprotective effect of 17β‐oestradiol in diabetic ischaemic stroke by modulating oestrogen receptor expression and the MAPK/ERK1/2 signalling pathway

The selective oestrogen receptor modulator, bazedoxifene, mimics the neuroprotective effect of 17β‐oestradiol in diabetic ischaemic stroke by modulating oestrogen receptor expression and the MAPK/ERK1/2 signalling pathway

Bazedoxifene Plays a Protective Role against Inflammatory Injury of Endothelial Cells by Targeting CD40

G Protein-Coupled Estrogen Receptor Protects From Angiotensin II-Induced Increases in Pulse Pressure and Oxidative Stress

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