Nicorandil reversed homocysteine-induced coronary microvascular dysfunction via regulating PI3K/Akt/eNOS pathway

Zhan, Biming; Xu, Zhihong; Zhang, Yang; Wan, Kefei; Deng, Han-Yue; Wang, Dimeng; Bao, Huihui; Wu, Qinghua; Hu, Xiaoyi; Wang, Hong; Huang, Xiao; Cheng, Xiaoshu

doi:10.1016/j.biopha.2020.110121

Cited by 28 publications

(21 citation statements)

References 28 publications

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“…Our results showed that phosphorylation of Akt at Thr308 equally plays a crucial role in NO production both in vitro and in vivo , revealing an important role of p‐Akt Thr 308 in maintaining vascular tone. Although only HUVECs were used in the cell experiments of the present study, to our knowledge, the other types of endothelial cells derived from different vascular tissues (veins or arteries) or different calibers (aorta or arteriole) exert similar Akt phosphorylation pattern [47–49].…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation of Akt at Thr308 regulates p‐eNOS Ser1177 during physiological conditions

et al. 2021

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Endothelial nitric oxide synthase (eNOS)-derived nitric oxide (NO) plays a crucial role in maintaining vascular homeostasis. As a hallmark of eNOS activation, phosphorylation of eNOS at Ser1177 induced by activated protein kinase B (PKB/Akt) is pivotal for NO production. The complete activation of Akt requires its phosphorylation of both Thr308 and Ser473. However, which site plays the main role in regulating phosphorylation of eNOS Ser1177 is still controversial. The purpose of the present study is to explore the specific regulatory mechanism of phosphorylated Akt in eNOS activation. Inhibition of Akt Thr308 phosphorylation by a specific inhibitor or by siRNA in vitro, led to a decrease in eNOS phosphorylation at Ser1177 and to lower NO concentration in the cell culture medium of HUVECs. Whereas, inhibiting p-Akt Ser473 had no effect on eNOS phosphorylation at Ser1177.Next, we administered mice with inhibitors to downregulate p-Akt Ser473 or Thr308 activity. Along with the inhibition of p-Akt Thr308, vascular p-eNOS Ser1177 protein was simultaneously downregulated in parallel with a decrease in plasma NO concentration. Additionally, we cultured HUVECs at various temperature conditions (37°C, 22°C, and 4°C). The results showed that p-Akt Ser473 was gradually decreased in line with the reduction in temperature, accompanied with increased levels of p-Akt Thr308 and p-eNOS Ser1177. Taken together, our study indicates that the phosphorylation of Akt at Thr308, but not at Ser473, plays a more significant role in regulating p-eNOS Ser1177 levels under physiological conditions.

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Section: Discussionmentioning

confidence: 99%

Phosphorylation of Akt at Thr308 regulates p‐eNOS Ser1177 during physiological conditions

et al. 2021

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“…As previously mentioned, nicorandil attenuates I/R injury in the myocardium and reduces apoptosis in the cardiomyocytes of rats with diabetic cardiomyopathy. In addition, nicorandil, as a drug that improves microvascular circulation [ 27 ], causes vasodilation through two pathways: first, it has a nitrate-like effect, providing NO, and second, it selectively opens ATP-sensitive potassium channels (K ATP ) in cell membranes and mitochondria [ 28 ]. Moreover, clinical studies have revealed that intracoronary injection of nicorandil prior to PCI for ST-segment elevation myocardial infarction (STEMI) significantly improved myocardial perfusion and reduced arrhythmias during PCI in patients with STEMI [ 29 ] and effectively reduced the incidence of adverse cardiovascular events.…”

Section: Discussionmentioning

confidence: 99%

Protective effect of ischaemic postconditioning combined with nicorandil on myocardial ischaemia‒reperfusion injury in diabetic rats

Xia

Chen

Zhou

et al. 2022

BMC Cardiovasc Disord

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Background The diabetic heart exhibits a high sensitivity to ischaemia/reperfusion (I/R) injury. Diabetes mellitus (DM) can affect the efficacy of cardioprotective interventions and reduce the therapeutic potential of existing treatment options. This study aimed to investigate the feasibility of shifting from monotherapy to combination therapy in diabetic myocardial I/R injury. Methods 6–8 week rats were randomized into 10 groups: sham, I/R, ischaemia postconditioning (I-Post), nicorandil (Nic), combination therapy (I-Post + Nic), DM sham, DM I/R, DM I-Post, DM Nic and DM I-Post + Nic. The extent of myocardial injury was clarified by measuring CK-MB and NO levels in plasma, ROS content in myocardial tissues, and TTC/Evans Blue staining to assess the area of myocardial infarction. Pathological staining of cardiac tissue sections were performed to clarify the structural changes in myocardial histopathology. Finally, Western blotting was performed to detect the phosphorylation levels of some key proteins in the PI3K/Akt signalling pathway in myocardial tissues. Results We confirms that myocardial injury in diabetic I/R rats remained at a high level after treatment with I-Post or nicorandil alone. I-Post combined with nicorandil showed better therapeutic effects in diabetic I/R rats, and the combined treatment further reduced the area of myocardial injury in diabetic I/R rats compared with I-Post or nicorandil treatment alone (P < 0.001), as well as the levels of the myocardial injury markers CK-MB and ROS (P < 0.001); it also significantly increased plasma NO levels. Pathological staining also showed that diabetic rats benefited significantly from the combination therapy. Further mechanistic studies confirmed this finding. The protein phosphorylation levels of PI3K/Akt signalling pathway in the heart tissue of diabetic I/R rats were significantly higher after the combination treatment than after one treatment alone (all P < 0.05). Conclusion I-Post combined with nicorandil treatment maintains effective cardioprotection against diabetic myocardial I/R injury by activating the PI3K/Akt signalling pathway.

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“…The association between hsa_circ_0004543 and endothelial cell invasion was assessed by monitoring HUVEC invasion. NOS3 (also named eNOS) is an important downstream mediator of the PI3K/AKT pathway (Zhan et al, 2020). The PI3K enzyme is a kinase that catalyzes the phosphorylation of phosphoinositide and is widely expressed in various types of cells and participates in various biological processes.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of hsa_circ_0004543 Activates oxLDL-Induced Vascular Endothelial Cell Proliferation and Angiogenesis

Han

Hang

et al. 2021

Front. Genet.

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Circular RNAs (circRNAs) are novel non-coding RNAs, which show abnormal expression in several diseases, such as atherosclerosis (AS). The purpose of the present study was to reveal the association between hsa_circ_0004543 and AS. In the present study, hsa_circ_0004543 was overexpressed in human umbilical vein endothelial cells (HUVECs) induced by oxidized low-density lipoprotein (oxLDL). Inhibition of hsa_circ_0004543 expression facilitated the proliferation, migration, and invasion of HUVECs and significantly reduced their apoptotic rate following treatment with oxLDL. Furthermore, silencing of hsa_circ_0004543 activated the PI3K/AKT/NOS3 pathway in oxLDL-induced HUVECs. Collectively, these results demonstrated that hsa_circ_0004543 may play a vital role in the development of AS and affect the proliferation of HUVECs, providing a potential target for treating endothelial cell damage in AS.

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Nicorandil reversed homocysteine-induced coronary microvascular dysfunction via regulating PI3K/Akt/eNOS pathway

Cited by 28 publications

References 28 publications

Phosphorylation of Akt at Thr308 regulates p‐eNOS Ser1177 during physiological conditions

Phosphorylation of Akt at Thr308 regulates p‐eNOS Ser1177 during physiological conditions

Protective effect of ischaemic postconditioning combined with nicorandil on myocardial ischaemia‒reperfusion injury in diabetic rats

Downregulation of hsa_circ_0004543 Activates oxLDL-Induced Vascular Endothelial Cell Proliferation and Angiogenesis

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