Postconditioning inhibits myocardial apoptosis during prolonged reperfusion via a JAK2-STAT3-Bcl-2 pathway

<p>Abstract</p> <p>Background</p> <p>Postconditioning (PostC) inhibits myocardial apoptosis after ischemia-reperfusion (I/R) injury. The JAK2-STAT3 pathway has anti-apoptotic effects and plays an essential role in the late protection of preconditioning. Our aim was to investigate the anti-apoptotic effect of PostC after prolonged reperfusion and the role of the JAK2-STAT3 pathway in the anti-apoptotic effect of PostC.</p> <p>Methods</p> <p>Wistar rats were subjected to 30 minutes ischemia and 2 or 24 hours (h) reperfusion, with or without PostC (three cycles of 10 seconds reperfusion and 10 seconds reocclusion at the onset of reperfusion). Separate groups of rats were treated with a JAK2 inhibitor (AG490) or a PI3K inhibitor (wortmannin) 5 minutes before PostC. Immunohistochemistry was used to analyze Bcl-2 protein levels after reperfusion. mRNA levels of Bcl-2 were detected by qRT-PCR. TTC staining was used to detect myocardial infarction size. Myocardial apoptosis was evaluated by TUNEL staining. Western-blot was used to detect p-STAT3 and p-Akt levels after reperfusion.</p> <p>Results</p> <p>There was more myocardial apoptosis at 24 h <it>vs </it>2 h after reperfusion in all groups. PostC significantly reduced myocardial apoptosis and elevated Bcl-2 levels at both 2 and 24 hours after reperfusion. PostC increased p-STAT3 and p-Akt levels after reperfusion. Administration of AG490 reduced p-STAT3 and p-Akt levels and attenuated the anti-apoptotic effect of PostC. Wortmannin also reduced p-Akt levels and attenuated the anti-apoptotic effect of PostC but had no effect on p-STAT3 levels. AG490 abrogated the up-regulation of Bcl-2 by PostC.</p> <p>Conclusion</p> <p>PostC may reduce myocardial apoptosis during prolonged reperfusion via a JAK2-STAT3-Bcl-2 pathway. As a downstream target of JAK2 signaling, activation of PI3K/Akt pathway may be necessary in the protection of PostC.</p

Case Report: A FBN1 frameshift-and-nonsense mutation and aortic dissection in Marfan syndrome

BackgroundMarfan syndrome (MFS) is an autosomal dominant connective tissue disorder primarily affecting the cardiovascular, ocular, and skeletal systems. Cardiovascular complications are the leading cause of mortality in MFS. Mutations in the FBN1 gene, which encodes fibrillin-1, a critical extracellular matrix protein, are the predominant cause of the disorder.Case presentationOn March 11, 2024, we diagnosed a 30-year-old female proband with MFS based on the revised Ghent criteria, presenting with aortic root aneurysm, aortic dissection, multiple skeletal abnormalities, and a family history of MFS. Whole-exome sequencing followed by Sanger sequencing confirmation identified a novel inherited insertion mutation (c.4991dupA) in exon 40 of the FBN1 gene. We performed valve-sparing aortic root replacement (David Procedure) and total aortic arch replacement using a tetrafurcated graft, along with the implantation of a specially designed frozen elephant trunk in the descending aorta (Sun's Procedure). Postoperatively, the patient underwent biweekly clinical follow-ups for three months. No treatment-related adverse events were reported during the monitoring period.ConclusionThe diagnosis of MFS requires an integrated approach, combining clinical manifestations, imaging studies, and genetic analysis. This novel mutation is associated with severe skeletal manifestations and life-threatening cardiovascular abnormalities, underscoring its clinical relevance. Its association with aggressive phenotypes enhances genotype-phenotype correlations. Importantly, these findings highlight the imperative need for early intervention in high-risk individuals by bridging genetic discovery to clinical practice

The universal values of science and China’s Nobel Prize pursuit

China does not seem to believe the existence of universally acknowledged values in science and fails to promote the observation of such values that also should be applied to every member of the scientific community and at all times. Or, there is a separation between the practice of science in China and the values represented by modern science. In this context, science, including the pursuit of the Nobel Prize, is more a pragmatic means to achieve the end of the political leadership – the national pride in this case – than an institution laden with values that govern its practices. However, it is the recognition and respect of the latter that could lead to achievement of the former, rather than the other way around

Cytokine responses and anti-inflammatory strategies in Coronary Artery Bypass Grafting

It is well established that conventional coronary artery bypass grafting with cardiopulmonary bypass induces a systemic inflammatory response, but the mechanism involved is still less understood. The present series of studies was designed to define the cytokine responses and its relationship to myocardial dysfunction. The anti-inflammatory effect of aprotinin, estrodial and adenosine were evaluated in low-risk male CABG patients. The present studies confirmed that peripheral plasma levels of inflammatory cytokines IL-6, IL-8 and IL-10 are elevated after CABG with CPB, while off-pump CABG is accompanied with less cytokine responses and lesser myocardial injury. Further studies focus on stepwise analysis on the influence of different aspects associated with the CPB procedure are warranted. There was a trend towards higher peripheral cytokine levels in patients with impaired postoperative myocardial function. Peripheral cytokine levels were correlated to postoperative myocardial injury. However, regional cytokine levels might be more important in the mechanism involved in myocardial dysfunction. Pump prime aprotinin fails to limits the systemic cytokine response after CABG. This could be due to a dose-dependent phenomenon. However, lower leukocyte counts and IL-10 release after reperfusion were found in the aprotinin group compared to the controls. The anti-inflammatory effect of pump prime aprotinin need further evaluation. Pretreatment of two doses of 2 mg 17b-estradiol was proved to be safe for men during CABG in the present study. Leukocyte counts and plasma MPO levels were lower in patients with 17b-estradiol pretreatment, which indicate that estrogen limits leukocyte activation after CABG, but the present dose fails to limit systemic cytokine responses. A vasodilative effect of 17b-estradiol was observed after CABG, and this effect need further investigation. The present low dose adenosine pretreatment protocol (as compared to doses in the literature) reduces myocardial injury and improves cardiac function after CABG, but it failed in limiting systemic cytokine responses. However, four of the fifteen patients developed profound hypotension during the adenosine administration. This calls for further study to evaluate the safe protocol for adenosine pretreatment. A trend of lower systemic and myocardial neutrophil were observed in the adenosine patients, and further study is warranted to define whether adenosine may attenuate the neutrophil accumulation in myocardium after CABG.It is well established that conventional coronary artery bypass grafting with cardiopulmonary bypass induces a systemic inflammatory response, but the mechanism involved is still less understood. The present series of studies was designed to define the cytokine responses and its relationship to myocardial dysfunction. The anti-inflammatory effect of aprotinin, estrodial and adenosine were evaluated in low-risk male CABG patients. The present studies confirmed that peripheral plasma levels of inflammatory cytokines IL-6, IL-8 and IL-10 are elevated after CABG with CPB, while off-pump CABG is accompanied with less cytokine responses and lesser myocardial injury. Further studies focus on stepwise analysis on the influence of different aspects associated with the CPB procedure are warranted. There was a trend towards higher peripheral cytokine levels in patients with impaired postoperative myocardial function. Peripheral cytokine levels were correlated to postoperative myocardial injury. However, regional cytokine levels might be more important in the mechanism involved in myocardial dysfunction. Pump prime aprotinin fails to limits the systemic cytokine response after CABG. This could be due to a dose-dependent phenomenon. However, lower leukocyte counts and IL-10 release after reperfusion were found in the aprotinin group compared to the controls. The anti-inflammatory effect of pump prime aprotinin need further evaluation. Pretreatment of two doses of 2 mg 17b-estradiol was proved to be safe for men during CABG in the present study. Leukocyte counts and plasma MPO levels were lower in patients with 17b-estradiol pretreatment, which indicate that estrogen limits leukocyte activation after CABG, but the present dose fails to limit systemic cytokine responses. A vasodilative effect of 17b-estradiol was observed after CABG, and this effect need further investigation. The present low dose adenosine pretreatment protocol (as compared to doses in the literature) reduces myocardial injury and improves cardiac function after CABG, but it failed in limiting systemic cytokine responses. However, four of the fifteen patients developed profound hypotension during the adenosine administration. This calls for further study to evaluate the safe protocol for adenosine pretreatment. A trend of lower systemic and myocardial neutrophil were observed in the adenosine patients, and further study is warranted to define whether adenosine may attenuate the neutrophil accumulation in myocardium after CABG