Changyun Liu

Cardiac ischemia/reperfusion (I/R) injury is an important therapeutic target for ischemic heart disease. Lipid droplets (LDs) are the key organelles involved in lipid metabolism. This study aimed to identify the LD‐mediated protection against lipotoxicity in cardiac I/R injury. LD accumulation is upregulated in hearts subjected to I/R injury; however, it is insufficient to neutralize lipotoxicity or prevent cardiomyocyte death. Seipin played a central role in LD biogenesis in cardiomyocytes following I/R injury. Seipin deficiency led to reduced LD levels and exacerbated cardiac I/R injury. Whereas increased LD levels, via Seipin overexpression or lipolysis inhibition, ameliorated myocardial I/R injury. I/R‐induced downregulation of Seipin is attributed to the reduced expression of its transcription factor USF1, which is required for metabolic adaptation in acute myocardial ischemia. These findings not only elucidate the pathophysiological roles of LDs and Seipin but also provide a promising therapeutic target for myocardial I/R injury.

BACKGROUND: Cardiac ischemia/reperfusion (I/R) injury has emerged as an important therapeutic target for ischemic heart disease. Currently, there is no effective therapy for reducing cardiac I/R injury. Damage-associated molecular patterns are endogenous molecules released after cellular damage to exaggerate tissue inflammation and injury. RIPK3 (receptor-interacting protein kinase 3), a well-established intracellular mediator of cell necroptosis and inflammation, serves as a circulating biomarker of multiple diseases. However, whether extracellular RIPK3 also exerts biological functions in cardiac I/R injury remains totally unknown. METHODS: Patients with acute myocardial infarction receiving percutaneous coronary intervention (PCI) were recruited independently in the discovery cohort (103 patients) and validation cohort (334 patients), and major adverse cardiovascular events were recorded. Plasma samples were collected before and after PCI (6 and 24 h) for RIPK3 concentration measurement. Cultured neonatal rat ventricular myocytes, macrophages and endothelial cells, and in vivo mouse models with myocardial injury induced by I/R (or hypoxia/reoxygenation) were used to investigate the role and mechanisms of extracellular RIPK3. Another cohort including patients with acute myocardial infarction receiving PCI and healthy volunteers was recruited to further explore the mechanisms of extracellular RIPK3. RESULTS: In the discovery cohort, elevated plasma RIPK3 levels after PCI are associated with poorer short- and long-term outcomes in patients with acute myocardial infarction, as confirmed in the validation cohort. In both cultured cells and in vivo mouse models, recombinant RIPK3 protein exaggerated myocardial I/R (or hypoxia/reoxygenation) injury, which was alleviated by the RIPK3 antibody. Mechanistically, RIPK3 acted as a damage-associated molecular pattern and bound with RAGE (receptor of advanced glycation end-products), subsequently activating CaMKII (Ca ²⁺ /calmodulin-dependent kinase II) to elicit the detrimental effects. The positive correlation between plasma RIPK3 concentrations and CaMKII phosphorylation in human peripheral blood mononuclear cells was confirmed. CONCLUSIONS: We identified the positive relationship between plasma RIPK3 concentrations and the risk of major adverse cardiovascular events in patients with acute myocardial infarction receiving PCI. As a damage-associated molecular pattern, extracellular RIPK3 plays a causal role in multiple pathological conditions during cardiac I/R injury through RAGE/CaMKII signaling. These findings expand our understanding of the physiological and pathological roles of RIPK3, and also provide a promising therapeutic target for myocardial I/R injury and the associated complications.

Objective: To explore the diagnostic value of third ventricle width (TVW) measured by transcranial ultrasound (TCS) in the clinical diagnosis of Alzheimer's disease (AD) by analyzing and comparing the image characteristics of TVW in AD patients and healthy controls, and its correlation with cranial magnetic resonance medial temporal lobe atrophy (MTA) visual score and neuropsychological characteristics. Methods: TCS examination, MTA score and neuropsychological tests were performed in 39 confirmed AD and 41 normal controls from the Second Affiliated Hospital of Soochow University between January and July 2021. The correlation of TVW with MTA score and neuropsychological characteristics was analyzed and compared between the two groups. Results: A total of thirty-nine AD patients were enrolled, with 28 males and 11 females, aged (73±9) years, including 18 mild, 20 moderate, and 1 severe AD patient. Meanwhile, 41 healthy controls were also included, with 24 males and 17 females, aged (69±6) years old. TVW in AD patients was significantly wider than that in normal controls [0.76(0.66, 0.87) cm vs 0.50(0.44, 0.56) cm, PPPPPPr=-0.339, P=0.035), delayed recall (r=-0.523, Pr=-0.409, P=0.045), visual space and executive function (r=-0.333, P=0.039), but positively correlated with the atrophy of the medial temporal lobe (r= 0.552, P<0.001). Conclusions: TCS can be used to measure TVW in AD patients. When combined with MTA score and neuropsychological tests, it can provide a reliable objective basis for the clinical diagnosis of AD.