Exendin-4 Ameliorates Cardiac Remodeling in Experimentally Induced Myocardial Infarction in Rats by Inhibiting PARP1/NF-κB Axis in A SIRT1-Dependent Mechanism

Eid, Refaat A.; Alharbi, Samah A.; El‐kott, Attalla F.; Eleawa, Samy M; Zaki, M. J.; El-Sayed, Fahmy; Eldeen, Muhammad Alaa; Aldera, Hussain; Al‐Shudiefat, Abd Al‐Rahman

doi:10.1007/s12012-020-09567-5

Cited by 19 publications

(19 citation statements)

References 54 publications

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“…To test whether the efficiency of AG is mediated directly through their GSHR1a receptors and by activating SIRT1, we evaluated all the beneficial effects in the same animal model which was treated with AG and co‐treated with EX‐527, a SIRT1 inhibitor and [D‐Lys3]‐GHRP‐6 and GSHR1a antagonist. The in vivo use of both inhibitors is well documented in vivo and in vivo in rodents including rats 50,51,76‐78 . On the one hand, EX‐527, the most commonly used SIRT1 inhibitor, has high potency with significant isoform selectivity 77 .…”

Section: Discussionmentioning

confidence: 99%

“…EX‐527 is more selective (200‐ to 500‐fold) for SIRT1 than for SIRT2 or SIRT3. The dose of EX‐527 was adopted from similar in vivo studies in rats, which have shown effectiveness of this dose to completely inhibit SIRT1 without obvious side effects 51 . Besides, in our preliminary data, we noticed that 3 weeks after the last dose of DOX was sufficient to induce severe renal damage and impaired dysfunction, a period that was selected for this study.…”

Section: Methodsmentioning

confidence: 98%

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Acylated ghrelin protects against doxorubicin‐induced nephropathy by activating silent information regulator 1

Shati

El‐kott

2021

Basic Clin Pharma Tox

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This study investigated the nephroprotective role of acylated ghrelin (AG) against DOX‐induced nephropathy and examined whether the protection involves silent information regulator 1 (SIRT1). Rats were divided into control, control + AG, DOX, DOX + AG, DOX + AG + [D‐Lys3]‐GHRP‐6 (a ghrelin receptor antagonist), and DOX + AG + EX‐527 (a sirt1 inhibitor). DOX was given over the first 2 weeks. AG (10 ng/kg) and both inhibitors were given as 3 doses/wk for 5 weeks. AG improved the structure and the function of the kidneys; down‐regulated the renal expression of TGF‐β1, collagen 1A1 and α‐SMA; and inhibited the renal collagen deposition in the kidneys of DOX‐treated rats. Concomitantly, it reduced the renal levels of ROS, MDA, TNF‐α, and IL‐6 and protein levels of cytochrome‐c, TGF‐β1, Smad3 and α‐SMA in these rats. In both the control and DOX‐treated rats, AG significantly increased the renal levels of SOD and GSH, decreased the expression of cleaved caspase‐3 and Bax, increased the total levels and the nuclear activity of SIRT1 and reduced the deacetylation of p53, NF‐κB and FOXO‐31. All the effects were abolished by the concurrent administration of EX‐527 and [D‐Lys3]‐GHRP‐6. In conclusion, AG prevents DOX‐induced nephropathy in SIRT1 and GSHRa1‐dependent mechanism.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 98%

Acylated ghrelin protects against doxorubicin‐induced nephropathy by activating silent information regulator 1

Shati

El‐kott

2021

Basic Clin Pharma Tox

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“…Recent studies have proved that PARP1 inhibition can protect diabetic heart via activating SIRT1-PGC1 alpha axis ( Waldman et al, 2018 ); Through activating SIRT1-induced inhibition of PARP1, post myocardial infarction infammation and cardiac remodeling can be prevented ( Eid et al, 2020 ). Apart from cardiovascular diseases, deficiency of PARP1 can also alleviate pulmonary fibrosis ( Zhang et al, 2018 ), while PARP1 overactivation can lead to hepatic fibrosis ( Mukhopadhyay et al, 2014 ).…”

Section: Discussionmentioning

confidence: 99%

Sp1 Targeted PARP1 Inhibition Protects Cardiomyocytes From Myocardial Ischemia–Reperfusion Injury via Downregulation of Autophagy

Wang

Liu

et al. 2021

Front. Cell Dev. Biol.

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Myocardial ischemia–reperfusion injury (MIRI), characterized by post-ischemic cardiomyocytes death and reperfusion myocardial damage, is a lethal yet unresolved complication in the treatment of acute myocardial infarction (AMI). Previous studies have demonstrated that poly(ADP-ribose) polymerase-1 (PARP1) participates in the progression of various cardiovascular diseases, and various reports have proved that PARP1 can be a therapeutic target in these diseases, but whether it plays a role in MIRI is still unknown. Therefore, in this study, we aimed to explore the role and mechanism of PARP1 in the development of MIRI. Firstly, we demonstrated that PARP1 was activated during MIRI-induced myocardial autophagy in vitro. Moreover, PARP1 inhibition protected cardiomyocytes from MIRI through the inhibition of autophagy. Next, we discovered that specificity protein1 (Sp1), as a transcription factor of PARP1, regulates its target gene PARP1 through binding to its target gene promoter during transcription. Furthermore, silencing Sp1 protected cardiomyocytes from MIRI via the inhibition of PARP1. Finally, the functions and mechanisms of PARP1 in the development of MIRI were also verified in vivo with SD rats model. Based on these findings, we concluded that PARP1 inhibition protects cardiomyocytes from MIRI through the inhibition of autophagy, which is targeted by Sp1 suppression. Therefore, the utilization of PARP1 exhibits great therapeutic potential for MIRI treatment in future.

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“…The induction of MI was introduced to the rats by ligating the LAD coronary artery as previously described by Eid et al (2020) . In brief, each rat was anesthetized using 1.9 mg/kg ketamine/xylazine hydrochloride solution.…”

Section: Methodsmentioning

confidence: 99%

“…By the end of day 30 and over 3 days, the rats were anesthetized by 60 mg/kg of 1% sodium pentobarbital solution, i.p. LV function was studied using a Millar catheter and a Powerlab system (Model ML780, ADInstruments, Australia) and analyzed using LabChart 8 (ADInstruments, Australia) as previously described by Eid et al (2020) . The measured hemodynamic parameters were 1) LVSP: LV systolic pressure, 2) dP/dt max : maximum derivative of the change in systolic pressure over time, 3) dP/dt min : minimum derivative of the change in diastolic pressure; and 4) LVEDP: LV end-diastolic pressure.…”

Section: Methodsmentioning

confidence: 99%

Quercetin prevents myocardial infarction adverse remodeling in rats by attenuating TGF-β1/Smad3 signaling: Different mechanisms of action

Albadrani

BinMowyna

Bin-Jumah

et al. 2021

Saudi Journal of Biological Sciences

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This study investigated the anti-remodeling and anti-fibrotic and effect of quercetin (QUR) in the remote non-infarcted of rats after myocardial infarction (MI). Rats were divided as control, control + QUR, MI, and MI + QUR. MI was introduced to the rats by ligating the eft anterior descending (LAD) coronary artery. All treatments were given for 30 days, daily. QUR persevered the LV hemodynamic parameters and prevented remote myocardium damage and fibrosis. Also, QUR supressed the generation of ROS, increased the nuclear levels of Nrf2, and enhanced SOD and GSH levels in the LVs of the control and MI model rats. It also reduced angiotensin II, nuclear level/activity of the nuclear factor NF-κβ p65, and protein expression of TGF-β1, α-SMA, and total/phospho-smad3 in the LVs of both groups. Concomitantly, QUR upregulated LV smad7 and BMP7. In conclusion, QUR prevents MI-induced LV remodeling by antioxidant, anti-inflammatory, and anti-fibroticα effects mediated by ROS scavenging, suppressing NF-κβ, and stimulating Nrf-2, Smad7, and BMP7.

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Exendin-4 Ameliorates Cardiac Remodeling in Experimentally Induced Myocardial Infarction in Rats by Inhibiting PARP1/NF-κB Axis in A SIRT1-Dependent Mechanism

Cited by 19 publications

References 54 publications

Acylated ghrelin protects against doxorubicin‐induced nephropathy by activating silent information regulator 1

Acylated ghrelin protects against doxorubicin‐induced nephropathy by activating silent information regulator 1

Sp1 Targeted PARP1 Inhibition Protects Cardiomyocytes From Myocardial Ischemia–Reperfusion Injury via Downregulation of Autophagy

Quercetin prevents myocardial infarction adverse remodeling in rats by attenuating TGF-β1/Smad3 signaling: Different mechanisms of action

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