Depressed calcium cycling contributes to lower ischemia tolerance in hearts of estrogen-deficient rats

Dunay, Gábor A.; Paragi, Péter; Sára, Levente; Ács, Nándor; Balázs, Bernadett; Agoston, Viktor A.; Repas, Csaba; Ivanics, Tamás; Miklós, Zsuzsanna

doi:10.1097/gme.0000000000000377

Cited by 12 publications

(12 citation statements)

References 45 publications

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“…Diastolic function in the post-ischemic phase is represented by the LVEDP value (i.e., contracture state). In our experiments, contracture was evaluated only after ischemia, although during ischemia an increase of contracture was observed, as reported by Dunay et al (2015). pGlu-Serp infusion before ischemia significantly reduced LVEDP in SHR_pGlu-Serp-Pre group compared to the respective Control counterpart (p<0.05 vs. SHR_Control).…”

Section: Resultssupporting

confidence: 67%

pGlu-serpinin protects the normotensive and hypertensive heart from ischemic injury

Pasqua¹,

Tota²,

Penna³

et al. 2015

Journal of Endocrinology

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Serpinin peptides derive from proteolytic cleavage of Chromogranin-A at C-terminus. Serpinin and the more potent pyroglutaminated-Serpinin (pGlu-Serp) are positive cardiac beta-adrenergic-like modulators, acting through β1-AR/AC/cAMP/PKA pathway. Since in some conditions this pathway and/or other pro-survival pathways, activated by other Chromogranin-A fragments, may cross-talk and may be protective, here we explored whether pGlu-Serp cardioprotects against ischemia/reperfusion injury under normotensive and hypertensive conditions. In the latter condition cardioprotection is often blunted because of the limitations on pro-survival Reperfusion-Injury-Salvage-Kinases (RISK) pathway activation. The effects of pGlu-Serp were evaluated on infarct size (IS) and cardiac function by using the isolated and Langendorff perfused heart of normotensive (WKY) and spontaneously hypertensive (SHR) rats exposed to ischemic pre-conditioning (PreC) and post-conditioning (PostC). In both WKY and SHR rat, pGlu-Serp induced mild cardioprotection in both PreC and in PostC. pGlu-Serp administered at the reperfusion (Serp-PostC) significantly reduced IS, being more protective in SHR than in WKY. Conversely, developed Left Ventricular Pressure (LVDevP) post-ischemic recovery was greater in WKY than in SHR. pGlu-Serp-PostC reduced contracture in both strains. Co-infusion with specific RISK inhibitors (PI3K/AkT, MitoKATP channels, and PKC) blocked the pGlu-Serp-PostC protective effects. To show direct effect on cardiomyocytes, we pre-treated H9c2 with pGlu-Serp which were thus protected against hypoxia/reoxygenation. These results suggest pGlu-Serp as a potential modulatory agent implicated in the protective processes which can limit infarct size and overcome the hypertension-induced failure of PostC.

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Section: Resultssupporting

confidence: 67%

pGlu-serpinin protects the normotensive and hypertensive heart from ischemic injury

Pasqua¹,

Tota²,

Penna³

et al. 2015

Journal of Endocrinology

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“…Our results clearly demonstrated that an impairment in cardiac contractile function, including decreased fractional shortening and mitral valve E/A ratio, was observed in estrogen-deprived rats and obese-insulin resistant rats, whereas the impairment of cardiac ]i regulation in either estrogen deprivation condition or obesity alone (Apaijai et al, 2014;Bupha-Intr & Wattanapermpool, 2006;Dunay et al, 2015). However, our current study demonstrates that these deleterious effects were aggravated in obese-insulin resistant rats with estrogen deprivation, that is when both conditions were present.…”

Section: Discussionsupporting

confidence: 55%

“…This aggravation could be due to impairment in the expression of cardiac Ca 2+ handling proteins in obese‐insulin resistant rats with estrogen deprivation. Previous studies have shown that the expression of SERCA protein (Bupha‐Intr & Wattanapermpool, ; Dunay et al, ) and Ca 2+ uptake activities were decreased (Bupha‐Intr & Wattanapermpool, ) in ovariectomized rats. Our results demonstrated that SERCA, NCX and RYR expression were decreased in estrogen‐deprived rats and obese‐insulin resistant rats.…”

Section: Discussionmentioning

confidence: 96%

“…Cardiac contractile function is mainly regulated by intracellular calcium (Ca 2+ ) homeostasis which relies on cyclical changes in intracellular Ca 2+ concentration ([Ca 2+ ]i transient (Dunay et al, 2015). Three major cardiac Ca 2+ handling proteins including sarcoplasmic reticulum Ca 2+ -ATPase (SERCA), ryanodine receptor Ca 2+ release channel proteins (RYR) and Na + -Ca 2+ exchanger proteins (NCX) regulate [Ca 2+ ]i (Bupha-Intr & Wattanapermpool, 2006).…”

mentioning

confidence: 99%

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Estrogen deprivation aggravates intracellular calcium dyshomeostasis in the heart of obese‐insulin resistant rats

Palee

Minta

Mantor

et al. 2018

Journal Cellular Physiology

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The incidence of cardiovascular disease and metabolic syndrome increases after the onset of menopause, giving evidence for the vital role of estrogen. Intracellular calcium [Ca 2+ ]i regulation plays an important role in the maintenance of left ventricular (LV) contractile function. Although either estrogen deprivation or obesity has been shown to strongly affect the metabolic status and LV function, the effects of estrogen deprivation on the cardiometabolic status and cardiac [Ca 2+ ]i regulation in the obese-insulin resistant condition have never been investigated. Our hypothesis was that estrogen deprivation aggravates LV dysfunction through the increased impairment of [Ca 2+ ]i homeostasis in obese-insulin resistant rats. Female rats were fed on either a high-fat (HFD, 59.28% fat) or normal (ND, 19.77% fat) diet for 13 weeks. Then, rats were divided into sham (HFS and NDS) operated or ovariectomized (HFO and NDO) groups. Six weeks after surgery, metabolic status, LV function and incidence of [Ca 2+ ]i transients were determined. NDO, HFS, and HFO rats had evidence of obese-insulin resistance indicated by increased body weight with hyperinsulinemia and euglycemia. Although NDO, HFS, and HFO rats had markedly reduced %LV fractional shortening, E/A ratio and decreased [Ca 2+ ]i transient amplitude and decay rate, HFO rats had the most severe impairments. These findings indicate that estrogen deprivation had a strong impact on abnormal LV function through [Ca 2+ ]i regulation. In addition, evidence was found that in obese-insulin resistant rats, estrogen deprivation severely aggravates LV dysfunction via increased impairment of [Ca 2+ ]i homeostasis.

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“…However, in other studies, no change was observed in the expression of NCX expression in both oestrogen treatment and OVX animals . Although oestrogen decreased the expression of PLB, and OVX increased its expression, no change in expression was found in other reports . On the other hand, oestrogen downregulated the RyR expression, while in other reports both OVX and oestrogen treatments had no effect on RyR expression .…”

Section: Ers and βArs As Coregulators Of Cardiac Ca2+‐handling Proteinsmentioning

confidence: 74%

Molecular pathways of oestrogen receptors and β‐adrenergic receptors in cardiac cells: Recognition of their similarities, interactions and therapeutic value

et al. 2017

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Oestrogen receptors (ERs) and β‐adrenergic receptors (βARs) play important roles in the cardiovascular system. Moreover, these receptors are expressed in cardiac myocytes and vascular tissues. Numerous experimental observations support the hypothesis that similarities and interactions exist between the signalling pathways of ERs (ERα, ERβ and GPR30) and βARs (β1AR, β2AR and β3AR). The recently discovered oestrogen receptor GPR30 shares structural features with the βARs, and this forms the basis for the interactions and functional overlap. GPR30 possesses protein kinase A (PKA) phosphorylation sites and PDZ binding motifs and interacts with A‐kinase anchoring protein 5 (AKAP5), all of which enable its interaction with the βAR pathways. The interactions between ERs and βARs occur downstream of the G‐protein‐coupled receptor, through the Gαs and Gαi proteins. This review presents an up‐to‐date description of ERs and βARs and demonstrates functional synergism and interactions among these receptors in cardiac cells. We explore their signalling cascades and the mechanisms that orchestrate their interactions and propose new perspectives on the signalling patterns for the GPR30 based on its structural resemblance to the βARs. In addition, we explore the relevance of these interactions to cell physiology, drugs (especially β‐blockers and calcium channel blockers) and cardioprotection. Furthermore, a receptor‐independent mechanism for oestrogen and its influence on the expression of βARs and calcium‐handling proteins are discussed. Finally, we highlight promising therapeutic avenues that can be derived from the shared pathways, especially the phosphatidylinositol‐3‐OH kinase (PI3K/Akt) pathway.

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Depressed calcium cycling contributes to lower ischemia tolerance in hearts of estrogen-deficient rats

Cited by 12 publications

References 45 publications

pGlu-serpinin protects the normotensive and hypertensive heart from ischemic injury

pGlu-serpinin protects the normotensive and hypertensive heart from ischemic injury

Estrogen deprivation aggravates intracellular calcium dyshomeostasis in the heart of obese‐insulin resistant rats

Molecular pathways of oestrogen receptors and β‐adrenergic receptors in cardiac cells: Recognition of their similarities, interactions and therapeutic value

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