Pinacidil-postconditioning is equivalent to ischemic postconditioning in defeating cardiac ischemia-reperfusion injury in rat

Yang, Yi; Chen, Wei; Wang, Ying; Cao, Song; Yu, Tian; Wang, Haiying

doi:10.1016/j.ejphar.2016.03.027

Cited by 11 publications

(18 citation statements)

References 28 publications

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“…donor heart preservation. Our previous study confirmed that pinacidil postconditioning (PPC) at different concentrations inhibits IR injury in rats, primarily by upregulating nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream genes, such as NADH-quinone oxidoreductase-1 (NQO1), heme oxygenase 1 (HO-1) and superoxide dismutase 1 (SOD1), all of which serve important roles in myocardial protection (9). However, our study did not investigate the myocardial protective effects of different pinacidil concentrations or the association between pinacidil and reactive oxygen species (ROS), which are an important component in myocardial protective signaling.…”

Section: Ros-associated Mechanism Of Different Concentrations Of Pinacidil Postconditioning In the Rat Cardiac Nrf2-are Signaling Pathwaymentioning

confidence: 63%

ROS‑associated mechanism of different concentrations of pinacidil postconditioning in the rat cardiac Nrf2‑ARE signaling pathway

et al. 2021

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Previous studies have confirmed that 50 µmol/l pinacidil postconditioning (PPC) activates the nuclear factor-E2 related factor 2 (Nrf2)-antioxidant responsive element (ARE) pathway, which protects the myocardium from ischemia-reperfusion (IR) injury; however, whether this is associated with reactive oxygen species (ROS) generation remains unclear. In the present study, a Langendorff rat model of isolated myocardial IR was established to investigate the mechanism of PPC at different concentrations, as well as the association between the rat myocardial Nrf2-ARE signaling pathway and ROS. A total of 48 rats were randomly divided into the following six groups (n=8 per group): i) Normal; ii) IR iii) 10 µmol/l PPC (P10); iv) 30 µmol/l PPC (P30); v) 50 µmol/l PPC (P50); and vi) N-(2-mercaptopropionyl)-glycine (MPG; a ROS scavenger) + 50 µmol/l pinacidil (P50 + MPG). At the end of reperfusion (T3), compared with the IR group, the P10, P30 and P50 groups exhibited improved cardiac function, such as left ventricular development pressure, heart rate, left ventricular end-diastolic pressure, +dp/dtmax, myocardial cell ultrastructure and mitochondrial Flameng score. Furthermore, the P10 and P50 groups demonstrated the weakest and most marked improvements, respectively. Additionally, in the P10, P30 and P50 groups, the residual ROS content at the end of reperfusion was highly negatively correlated with relative expression levels of Nrf2 gene and protein. Higher pinacidil concentration was associated with higher ROS generation at 5 min post-reperfusion (T2), although this was significantly lower compared with the IR group, as well as with increased expression levels of antioxidant proteins and phase II detoxification enzymes downstream of the Nrf2 and Nrf2-ARE pathways. This result was associated with a stronger ability to scavenge ROS during reperfusion, leading to lower levels of ROS at the end of reperfusion (T3) and less myocardial damage. The optimal myocardial protective effect was achieved by 50 mmol/l pinacidil. However, cardiac function of the P50 + MPG group was significantly decreased, ultrastructure of cardiomyocytes was significantly impaired and the relative expression levels of genes and proteins in the Nrf2-ARE pathway were decreased. The aforementioned results confirmed that different PPC concentrations promoted early generation of ROS and activated the Nrf2-ARE signaling pathway following reperfusion, regulated expression levels of downstream antioxidant proteins and alleviated myocardial IR injury in rats. Treatment with 50 mmol/l pinacidil resulted in the best myocardial protection.

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Section: Ros-associated Mechanism Of Different Concentrations Of Pinacidil Postconditioning In the Rat Cardiac Nrf2-are Signaling Pathwaymentioning

confidence: 63%

ROS‑associated mechanism of different concentrations of pinacidil postconditioning in the rat cardiac Nrf2‑ARE signaling pathway

et al. 2021

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“…Ischemic preconditioning and ischemic post-conditioning are effective methods to protect myocardial tissue against MIRI [ 94 ]. Apart from these, after posttreatment with pinacidil, the expressions of Nrf2, HO-1, NQO1, and SOD1 in rat are increased, thus significantly reducing the area of MI [ 98 ]. Moreover, hyperbaric oxygen preconditioning prevents MIRI by activating the PI3K/AKT/Nrf2 antioxidant defensive system [ 99 ].…”

Section: Nrf2 Signaling Pathway and Cvdmentioning

confidence: 99%

Role of Nrf2 and Its Activators in Cardiocerebral Vascular Disease

Cheng

Zhang

et al. 2020

Oxidative Medicine and Cellular Longevity

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Cardiocerebral vascular disease (CCVD) is a common disease with high morbidity, disability, and mortality. Oxidative stress (OS) is closely related to the progression of CCVD. Abnormal redox regulation leads to OS and overproduction of reactive oxygen species (ROS), which can cause biomolecular and cellular damage. The Nrf2/antioxidant response element (ARE) signaling pathway is one of the most important defense systems against exogenous and endogenous OS injury, and Nrf2 is regarded as a vital pharmacological target. The complexity of the CCVD pathological process and the current difficulties in conducting clinical trials have hindered the development of therapeutic drugs. Furthermore, little is known about the role of the Nrf2/ARE signaling pathway in CCVD. Clarifying the role of the Nrf2/ARE signaling pathway in CCVD can provide new ideas for drug design. This review details the recent advancements in the regulation of the Nrf2/ARE system and its role and activators in common CCVD development.

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“…research into alleviating Miri has demonstrated that, numerous methods, such as ischemic pre-conditioning, ischemic post-conditioning, drug pre-conditioning and drug post-conditioning can play a role in myocardial protection (3)(4)(5)(6)(7). at the same time, a variety of myocardial protection mechanisms are involved.…”

Section: Introductionmentioning

confidence: 99%

Mechanism of the hypoxia inducible factor 1/hypoxic response element pathway in rat myocardial ischemia/diazoxide post‑conditioning

et al. 2020

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ischemic post-conditioning (iPo) and diazoxide post-conditioning (dPo) has been proven to reduce myocardial ischemia reperfusion injury (Miri); however, the mechanisms of iPo/dPo are still not clear. The present study aimed to investigate whether mitochondrial aTP-sensitive potassium channels (mitoK aTP) channels are activated by iPo/dPo, which may further activate the hypoxia inducible factor 1/hypoxic response element (HiF-1/Hre) pathway to mitigate Miri. using a langendorff perfusion device, healthy male (250-300 g) Sprague dawley rat hearts were randomly divided into the following groups. Group n was aerobically perfused with K-H solution for 120 min. Group ischaemia/reperfusion (i/r) was aerobically perfused for 20 min, then subjected to 40 min hypoxia plus 60 min reperfusion. Group iPo was treated like the i/r group, but with 10 sec of hypoxia plus 10 sec of reperfusion for six rounds before reperfusion. Group dPo was exposed to 50 µM diazoxide for 5 min before reperfusion and otherwise treated the same as group i/r. in groups iPo+5-hydroxydecanoic acid (5Hd), dPo+5Hd and i/r+5Hd, exposure to 100 µM 5Hd (a mitoK aTP channel specific blocker) for 5 min before reperfusion as described for groups iPo, dPo and i/r, respectively. in groups iPo+2-methoxyestradiol (2Me2), dPo+2Me2 and i/r+2Me2, exposure to 2 µM 2Me2 (a HiF-1α specific blocker) for 10 min before reperfusion as described for groups iPo, dPo and i/r respectively. cardiac hemodynamics, myocardial injury and the expression of HiF-1/Hre pathway [HiF-1α, heme oxygenase (Ho-1), inducible nitric oxide synthase (inoS) and vascular endothelial growth factor (VeGF)] were detected in each group. The infarct size and mitochondrial Flameng scores of groups IPO/DPO were significantly decreased compared with the i/r group (P<0.05), but the myocardial protective effects of iPo/dPo could be eliminated by 5Hd or 2Me2 (P<0.05). in addition, iPo/dPo could increase the mrna expression of HiF-1α and the downstream factors of the HiF-1/Hre pathway (the mrna and protein expression of Ho-1, inoS and VeGF; P<0.05). However, the myocardial protective effects and the activation the HiF-1/Hre pathway mediated by iPo/dPo could be eliminated by 5Hd or 2Me2 (P<0.05). Therefore, the activation of the HiF-1/Hre pathway by opening mitoK aTP channels may work with the mechanism of iPo/dPo in reducing Miri.

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Pinacidil-postconditioning is equivalent to ischemic postconditioning in defeating cardiac ischemia-reperfusion injury in rat

Cited by 11 publications

References 28 publications

ROS‑associated mechanism of different concentrations of pinacidil postconditioning in the rat cardiac Nrf2‑ARE signaling pathway

ROS‑associated mechanism of different concentrations of pinacidil postconditioning in the rat cardiac Nrf2‑ARE signaling pathway

Role of Nrf2 and Its Activators in Cardiocerebral Vascular Disease

Mechanism of the hypoxia inducible factor 1/hypoxic response element pathway in rat myocardial ischemia/diazoxide post‑conditioning

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