Exendin-4 Protects Against Myocardial Ischemia-Reperfusion Injury by Upregulation of SIRT1 and SIRT3 and Activation of AMPK
Exendin-4 通过上调 SIRT1 和 SIRT3 及激活 AMPK 保护心肌缺血再灌注损伤
- 作者列表："Eid, Refaat A.","Bin-Meferij, Mashael Mohammed","El-kott, Attalla Farag","Eleawa, Samy M","Zaki, Mohamed Samir Ahmed","Al-Shraim, Mubarak","El-Sayed, Fahmy","Eldeen, Muhammad Alaa","Alkhateeb, Mahmoud A.","Alharbi, Samah A.","Aldera, Hussain","Khalil, Mohammad A.
This study evaluated if the cardioprotective effect of Exendin-4 against ischemia/reperfusion (I/R) injury in male rats involves modulation of AMPK and sirtuins. Adult male rats were divided into sham, sham + Exendin-4, I/R, I/R + Exendin-4, and I/R + Exendin-4 + EX-527, a sirt1 inhibitor. Exendin-4 reduced infarct size and preserved the function and structure of the left ventricles (LV) of I/R rats. It also inhibited oxidative stress and apoptosis and upregulated MnSOD and Bcl-2 in their infarcted myocardium. With no effect on SIRTs 2/6/7, Exendin-4 activated and upregulated mRNA and protein levels of SIRT1, increased levels of SIRT3 protein, activated AMPK, and reduced the acetylation of p53 and PGC-1α as well as the phosphorylation of FOXO-1. EX-527 completely abolished all beneficial effects of Exendin-4 in I/R-induced rats. In conclusion, Exendin-4 cardioprotective effect against I/R involves activation of SIRT1 and SIRT3. Graphical Abstract Exendin-4 could scavenge free radical directly, upregulate p53, and through upregulation of SIRT1 and stimulating SIRT1 nuclear accumulation. In addition, Exendin-4 also upregulates SIRT3 which plays an essential role in the upregulation of antioxidants, inhibition of reactive oxygen species (ROS) generation, and prevention of mitochondria damage. Accordingly, SIRT1 induces the deacetylation of PGC-1α and p53 and is able to bind p-FOXO-1. This results in inhibition of cardiomyocyte apoptosis through increasing Bcl-2 levels, activity, and levels of MnSOD; decreasing expression of Bax; decreasing cytochrome C release; and improving mitochondria biogenesis through upregulation of Mfn-2.
本研究评估了 Exendin-4 对雄性大鼠缺血/再灌注 (I/R) 损伤的心脏保护作用是否涉及 AMPK 和 sirtuins 的调节。成年雄性大鼠分为 sham 、 sham + Exendin-4 、 I/R + Exendin-4 和 sirt1 抑制剂 I/R + Exendin-4 + EX-527。Exendin-4 缩小了 I/R 大鼠的梗死面积，保留了左心室的功能和结构。它还抑制氧化应激和细胞凋亡，上调梗死心肌 MnSOD 和 Bcl-2。对 SIRTs 2/6/7 没有影响，Exendin-4 激活并上调 SIRT1 的 mRNA 和蛋白水平，增加 SIRT3 蛋白水平，激活 AMPK,并降低 p53 和 pgc-1 α 的乙酰化以及 FOXO-1 的磷酸化。EX-527 完全消除了 Exendin-4 在 I/R 诱导大鼠中的所有有益作用。总之，对 I/R Exendin-4 的心脏保护作用涉及 SIRT1 和 sirt3 的激活。Exendin-4 可以直接清除自由基，上调 p53，并通过上调 SIRT1 和刺激 SIRT1 核积累。此外，Exendin-4 还上调 SIRT3，SIRT3 在抗氧化剂的上调，抑制活性氧 (ROS) 生成和防止线粒体损伤中起重要作用。因此，SIRT1 诱导 pgc-1 α 和 p53 的去乙酰化，并能够结合 p-FOXO-1。这导致通过增加 Bcl-2 水平、活性和 MnSOD 水平来抑制心肌细胞凋亡; 降低 Bax 的表达; 减少细胞色素 C 的释放; 并通过上调 Mfn-2 来改善线粒体的生物合成。
METHODS:BACKGROUND:Preterm birth is a risk factor for elevated blood pressure in childhood and the development of hypertension and cardiometabolic disease in adulthood; however, mechanisms for the development of both are poorly understood. Rapid weight gain early in childhood may serve as a driver directly and indirectly through cortisol levels found to be elevated in early childhood in individuals born preterm. OBJECTIVES:The objective of this pilot study was to examine the effect sizes of the relationships between weight gain and blood pressure in toddlers born very preterm. A secondary aim was to note any mediating effect of cortisol on the relationships between weight gain and blood pressure. METHODS:A cross-sectional design with a convenience sample of 36 toddlers who were born very preterm was used to examine the relationships between postnatal weight gain, cortisol, and blood pressure at follow-up. RESULTS:Many of the participants experienced rapid weight gain in the first 12 months of life. Mean systolic and diastolic readings were 94 and 56.6, respectively. Diastolic blood pressure readings were obtained from 23 participants and the majority were elevated. Weight gain was associated with diastolic blood pressure with a medium effect size. A mediating role with cortisol was not supported.Although findings need to be validated in a larger sample, the blood pressure elevations in this sample were alarming. If readings continue to amplify as these children age, the fact that elevations are already present during the toddler period could indicate more significant cardiovascular disease in adulthood for this population. Rapid weight gain in early life may be a driver for elevated blood pressure even during early childhood in individuals born preterm.
METHODS:This article presents a case series of n = 21 models of fetal cardiovascular anatomies obtained from post mortem microfocus computed tomography (micro-CT) data. The case series includes a broad range of diagnoses (e.g., tetralogy of Fallot, hypoplastic left heart syndrome, dextrocardia, double outlet right ventricle, atrio-ventricular septal defect) and cases also had a range of associated extra-cardiac malformations (e.g., VACTERL syndrome, central nervous system anomalies, renal anomalies). All cases were successfully reconstructed from the microfocus computed tomography data, demonstrating the feasibility of the technique and of the protocols, including in-house printing with a desktop 3D printer (Form2, Formlabs). All models were printed in 1:1 scale as well as with the 5-fold magnification, to provide insight into the intra-cardiac structures. Possible uses of the models include education and training.
METHODS:Abstract Background Congenital heart disease (CHD) affects ~ 1% of live births and is the most common birth defect. Although the genetic contribution to the CHD has been long suspected, it has only been well established recently. De novo variants are estimated to contribute to approximately 8% of sporadic CHD. Methods CHD is genetically heterogeneous, making pathway enrichment analysis an effective approach to explore and statistically validate CHD-associated genes. In this study, we performed novel gene and pathway enrichment analyses of high-impact de novo variants in the recently published whole-exome sequencing (WES) data generated from a cohort of CHD 2645 parent-offspring trios to identify new CHD-causing candidate genes and mutations. We performed rigorous variant- and gene-level filtrations to identify potentially damaging variants, followed by enrichment analyses and gene prioritization. Results Our analyses revealed 23 novel genes that are likely to cause CHD, including HSP90AA1, ROCK2, IQGAP1, and CHD4, and sharing biological functions, pathways, molecular interactions, and properties with known CHD-causing genes. Conclusions Ultimately, these findings suggest novel genes that are likely to be contributing to CHD pathogenesis.