AMPK upregulates KCa2.3 channels and ameliorates endothelial dysfunction in diet-induced obese mice

Pang, Zheng-Da; Wang, Yan; Song, Zheng; She, Gang; Ma, Xiao-Zhen; Sun, Xia; Wu, Wei; Lai, Baochang; Zhang, Jiao; Zhang, Yi; Du, Xiaolan; Shyy, John Y.‐J.; Deng, Xingming

doi:10.1016/j.bcp.2020.114337

Cited by 5 publications

(12 citation statements)

References 40 publications

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“…After cerebral ischemiareperfusion injury, the expression of phosphorylated ERK5 (p-ERK5) can be increased by activating the ERK5 signaling pathway, thereby inhibiting the transformation of Bad to a proapoptotic form, and playing an anti-apoptotic effect on neurons (Wang et al, 2006;Gu et al, 2017). ERK5 can activate Myocyte enhancer-binding factor 2 (MEF2) to give it transcriptional properties (Pang et al, 2020). This study found that after MCAO and OGD injury, the expression of MRF2A and the phosphorylation level of ERK5 decreased significantly.…”

Section: Discussionmentioning

confidence: 89%

Dexmedetomidine and Netrin-1 Combination Therapy Inhibits Endoplasmic Reticulum Stress by Regulating the ERK5/MEF2A Pathway to Attenuate Cerebral Ischemia Injury

Yin

Ren

et al. 2021

Front. Neurosci.

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The complexity of hard-to-treat diseases such as ischemic stroke strongly undermines the therapeutic potential of available treatment options. Therefore, current developments have gently shifted from a focus on monotherapy to combined or multiple therapies. Both dexmedetomidine and Netrin-1 have anti-neuronal apoptosis effects, but the mechanism is still unclear. The study aimed to estimate the efficacy of dexmedetomidine and Netrin-1 combination therapy against ERS-induced apoptosis after cerebral ischemia injury in vivo and in vitro, and whether the mechanism is related to the ERK5/MEF2A pathway. Adult male Sprague-Dawley rats were subjected to middle cerebral artery occlusion (MCAO) in vivo, 90 min ischemia and 24 h reperfusion. The hippocampus slices used to establish oxygen-glucose deprivation (OGD) injury model in vitro. Neterin-1 and Dexmedetomidine were pretreated and post-treated, respectively, before and after the model establishment. MEF2A knockdown was performed by microinjection of AAV9-MEF2A RNAi vector. Orthodromic population spike (OPS) at the end of reoxygenation were recorded. Neurobehavioral tests, TTC staining, Nissl staining, TUNEL staining were performed to assess the effect of the drugs. The expression of CHOP, GRP78, MEF2A, ERK5, and p-ERK5 were investigated by Western blot and immunofluorescence staining. Neurological deficit score, infarct volume, the expression of GRP78, CHOP, and neural apoptotic rate of MCAO group increased markedly. Combination of dexmedetomidine and Netrin-1 resulted in lower infarct volumes and fewer neurological impairments, higher OPS recovery rate, and less damaged and apoptotic cells after cerebral ischemia injury. Furthermore, expression levels of GRP78 and CHOP decreased in the combination therapy group, and it was more effective than the single drug group. Meanwhile, Combination of dexmedetomidine and Netrin-1 increased MEF2A expression and promoted ERK5 phosphorylation. However, the protective effect of dexmedetomidine combined with Netrin-1 in improving neurological function was significantly eliminated by pre-knockdown MEF2A. The neuroprotective effects of dexmedetomidine combined with Netrin on cerebral ischemia-reperfusion injury and hippocampal hypoxia injury in terms of ERS. The synergistic effect of combination therapy is related to the activation of ERK5/MEF2A signaling pathway.

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Section: Discussionmentioning

confidence: 89%

Dexmedetomidine and Netrin-1 Combination Therapy Inhibits Endoplasmic Reticulum Stress by Regulating the ERK5/MEF2A Pathway to Attenuate Cerebral Ischemia Injury

Yin

Ren

et al. 2021

Front. Neurosci.

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“…Nevertheless, the KCa‐dependent contribution to hindlimb blood flow response during skeletal muscle contractions was restored in our low‐intensity exercise trained fa/fa rats. An upregulation of KCa channels was partly confirmed by increased expression of KCNN3 proteins in the soleus muscle, which is reported to be a component of impaired EDH in the diabetic condition (Brøndum et al ., 2010; Burnham et al ., 2006; Pang et al ., 2021). Furthermore, it has been reported that activation of KCNN3 (SK3) contributes to exercise hyperaemia (Milkau et al ., 2010).…”

Section: Discussionmentioning

confidence: 99%

Increased contribution of KCa channels to muscle contraction induced vascular and blood flow responses in sedentary and exercise trained ZFDM rats

Sonobe

Tsuchimochi

Maeda

et al. 2022

The Journal of Physiology

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In resistance arteries, endothelium‐dependent hyperpolarization (EDH)‐mediated vasodilatation is depressed in diabetes. We hypothesized that downregulation of KCa channel derived EDH reduces exercise‐induced vasodilatation and blood flow redistribution in diabetes. To test this hypothesis, we evaluated vascular function in response to hindlimb muscle contraction, and the contribution of KCa channels in anaesthetised ZFDM, metabolic disease rats with type 2 diabetes. We also tested whether exercise training ameliorated the vascular response. Using in vivo microangiography, the hindlimb vasculature was visualized before and after rhythmic muscle contraction (0.5 s tetanus every 3 s, 20 times) evoked by sciatic nerve stimulation (40 Hz). Femoral blood flow of the contracting hindlimb was simultaneously measured by an ultrasonic flowmeter. The contribution of KCa channels was investigated in the presence and absence of apamin and charybdotoxin. We found that vascular and blood flow responses to muscle contraction were significantly impaired at the level of small artery segments in ZFDM fa/fa rats compared to its lean control fa/+ rats. The contribution of KCa channels was also smaller in fa/fa than in fa/+ rats. Low‐intensity exercise training for 12 weeks in fa/fa rats demonstrated minor changes in the vascular and blood flow response to muscle contraction. However, the KCa‐derived component in the response to muscle contraction was much greater in exercise trained than in sedentary fa/fa rats. These data suggest that exercise training increases the contribution of KCa channels among endothelium‐dependent vasodilatory mechanisms to maintain vascular and blood flow responses to muscle contraction in this metabolic disease rat model. Key points Microvascular dysfunction in type 2 diabetes impairs blood flow redistribution during exercise and limits the performance of skeletal muscle and may cause early fatigability. Endothelium‐dependent hyperpolarization (EDH), which mediates vasodilatation in resistance arteries, is known to be depressed in animals with diabetes. Here, we report that low‐intensity exercise training in ZFDM rats increased the KCa channel‐derived component in the vasodilator responses to muscle contraction compared to that in sedentary rats, partly as a result of the increase in KCNN3 expression. These results suggest that low‐intensity exercise training improves blood flow redistribution in contracting skeletal muscle in metabolic disease with diabetes via upregulation of EDH.

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“…Vascular reactivity was evaluated by measuring isometric force in wire myograph as previously described. 18,22…”

Section: Methodsmentioning

confidence: 99%

“…T6700; Sigma-Aldrich, a selective K Ca 3.1 channel blocker), respectively, for 30 minutes before measurement of endothelium-dependent vasodilation. 22 In another set of experiments, the cumulative concentration-response curve of NS309 (0.1 nM to 1.0 μM, no. N8161, Sigma-Aldrich, coactivator of K Ca 2.3 and K Ca 3.1 channel 22 ) in phenylephrine-precontracted segments was assessed.…”

Section: Methodsmentioning

confidence: 99%

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Endothelial K _Ca 3.1 and K _Ca 2.3 Mediate S1P (Sphingosine-1-Phosphate)–Dependent Vasodilation and Blood Pressure Homeostasis

Zhao

Wang

et al. 2023

ATVB

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Background: S1P (sphingosine-1-phosphate) has been reported to possess vasodilatory properties, but the underlying pathways are largely unknown. Methods: Isolated mouse mesenteric artery and endothelial cell models were used to determine S1P-induced vasodilation, intracellular calcium, membrane potentials, and calcium-activated potassium channels (K Ca 2.3 and K Ca 3.1). Effect of deletion of endothelial S1PR1 (type 1 S1P receptor) on vasodilation and blood pressure was evaluated. Results: Mesenteric arteries subjected to acute S1P stimulation displayed a dose-dependent vasodilation response, which was attenuated by blocking endothelial K Ca 2.3 or K Ca 3.1 channels. In cultured human umbilical vein endothelial cells, S1P stimulated immediate membrane potential hyperpolarization following activation of K Ca 2.3/K Ca 3.1 with elevated cytosolic Ca 2+ . Further, chronic S1P stimulation enhanced expression of K Ca 2.3 and K Ca 3.1 in human umbilical vein endothelial cells in dose- and time-dependent manners, which was abolished by disrupting either S1PR1-Ca 2+ signaling or downstream Ca 2+ -activated calcineurin/NFAT (nuclear factor of activated T-cells) signaling. By combination of bioinformatics-based binding site prediction and chromatin immunoprecipitation assay, we revealed in human umbilical vein endothelial cells that chronic activation of S1P/S1PR1 promoted NFATc2 nuclear translocation and binding to promoter regions of K Ca 2.3 and K Ca 3.1 genes thus to upregulate transcription of these channels. Deletion of endothelial S1PR1 reduced expression of K Ca 2.3 and K Ca 3.1 in mesenteric arteries and exacerbated hypertension in mice with angiotensin II infusion. Conclusions: This study provides evidence for the mechanistic role of K Ca 2.3/K Ca 3.1-activated endothelium-dependent hyperpolarization in vasodilation and blood pressure homeostasis in response to S1P. This mechanistic demonstration would facilitate the development of new therapies for cardiovascular diseases associated with hypertension.

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AMPK upregulates KCa2.3 channels and ameliorates endothelial dysfunction in diet-induced obese mice

Cited by 5 publications

References 40 publications

Dexmedetomidine and Netrin-1 Combination Therapy Inhibits Endoplasmic Reticulum Stress by Regulating the ERK5/MEF2A Pathway to Attenuate Cerebral Ischemia Injury

Dexmedetomidine and Netrin-1 Combination Therapy Inhibits Endoplasmic Reticulum Stress by Regulating the ERK5/MEF2A Pathway to Attenuate Cerebral Ischemia Injury

Increased contribution of KCa channels to muscle contraction induced vascular and blood flow responses in sedentary and exercise trained ZFDM rats

Endothelial K _Ca 3.1 and K _Ca 2.3 Mediate S1P (Sphingosine-1-Phosphate)–Dependent Vasodilation and Blood Pressure Homeostasis

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AMPK upregulates KCa2.3 channels and ameliorates endothelial dysfunction in diet-induced obese mice

Cited by 5 publications

References 40 publications

Dexmedetomidine and Netrin-1 Combination Therapy Inhibits Endoplasmic Reticulum Stress by Regulating the ERK5/MEF2A Pathway to Attenuate Cerebral Ischemia Injury

Dexmedetomidine and Netrin-1 Combination Therapy Inhibits Endoplasmic Reticulum Stress by Regulating the ERK5/MEF2A Pathway to Attenuate Cerebral Ischemia Injury

Increased contribution of KCa channels to muscle contraction induced vascular and blood flow responses in sedentary and exercise trained ZFDM rats

Endothelial K Ca 3.1 and K Ca 2.3 Mediate S1P (Sphingosine-1-Phosphate)–Dependent Vasodilation and Blood Pressure Homeostasis

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Endothelial K _Ca 3.1 and K _Ca 2.3 Mediate S1P (Sphingosine-1-Phosphate)–Dependent Vasodilation and Blood Pressure Homeostasis