Influence of FOSL1 Inhibition on Vascular Calcification and ROS Generation through Ferroptosis via P53-SLC7A11 Axis.

BACKGROUND: Vascular calcification during aging is highly prevalent in patients with cardiovascular disease; however, there is still no improvement in clarifying the development of vascular calcification. FOSL1 is a transcription regulator belonging to the AP-1 family, which has a unique function in vascular senescence, but its role in vascular calcification needs to be further explored. METHODS: Primary mouse vascular smooth muscle cells were isolated and used to construct a calcification model in vitro. Seven-week-old male C57BL/6 mice were used to build the vitD3-induced calcification model in vivo. qRT-PCR and western blot were used to verify the expression of FOSL1 and other genes expressed in vascular smooth muscle cells and aortas. The level of calcification was determined by Alizarin Red S (ARS) staining and the calcium content assay. The level of cellular GSH was detected by the GSH assay kit. RESULTS: Here, we report that FOSL1 was up-regulated after high-calcium/phosphate treatment in both the in vivo and in vitro vascular calcification models. Functional studies have shown that the reduction of FOSL1 attenuates ferroptosis and calcification in vascular smooth muscle cells, as indicated by ARS staining, calcium content assay, and western blot. The inhibition of FOSL1 downregulated the expression of bone-related molecules including Msh Homeobox 2 (MSX2) and tumor necrosis factor receptor superfamily, member 11b/osteoprotegerin (OPG), suggesting that FOSL1 promoted osteogenic differentiation of vascular smooth muscle cells. Furthermore, we found that the ferroptosis-inducing drug erastin can significantly accelerate calcification in the aortic ring while Ferrostatin-1 (fer-1), a drug to protect cells from ferroptosis, can alleviate calcification. Further experiments have shown that inhibiting FOSL1 can promote the expression of ferroptosis-related genes and attenuate calcification. Functionally, cellular GSH levels were increased after the reduction of FOSL1. CONCLUSIONS: In this study, we observed a significant protective effect when we reduced the expression of FOSL1 during vascular calcification, and this effect might regulate ferroptosis to a great extent.

Association of Body Mass Index and Acute Kidney Injury Incidence and Outcome: A Systematic Review and Meta-Analysis.

This study aims to provide pooled estimates for the incidence of acute kidney injury (AKI) in overweight, obese, and normal body mass index (BMI) patients, and to assess impact of BMI on mortality and chronic kidney disease (CKD) rates. We conducted literature search using online databases to analyze outcomes of BMI. This meta-analysis included 22 studies. Compared to normal BMI, underweight, overweight, or obese patients had higher risk of having AKI. Underweight individuals had 17% lower CKD risk (relative risk [RR]: 0.83, 95% confidence interval [CI]: 0.75, 0.90) while patients that were overweight (RR: 1.15, 95% CI: 1.08, 1.22) and obese (RR: 1.21, 95% CI: 1.10, 1.33) had higher risk of having CKD. Lower than normal BMI was associated with higher mortality risk (RR: 1.58, 95% CI: 1.35, 1.85), while being overweight or obese correlated with the decreased risk of mortality. An increased risk of AKI combined with an increased risk of mortality calls for renal protective strategies in subjects who are underweight at the time of hospital admission.

Age, GFR, and Ejection Fraction Score as a Good Predictor of Prognosis in Elderly Patients with Nonischemic Dilated Cardiomyopathy.

INTRODUCTION: Nonischemic dilated cardiomyopathy (NIDCM) is a heterogeneous disease, and patients still have high risk of sudden cardiac death even after receiving treatment. The Selvester QRS score and the ESTIMATED score reported as predictors contain many variables and are complex to calculate. There is a need for a simple predictive score to accurately assess prognosis in clinical practice. METHODS: A total of 953 elderly patients (age ≥60 years) diagnosed with NIDCM were enrolled from January 2010 to December 2019. In-hospital and long-term outcomes were studied. RESULTS: Univariate logistic regression analysis showed that the AGEF score was associated with in-hospital mortality (OR: 1.828; 95% CI: 1.559-2.144; p < 0.001). Receiver operator characteristic curve analysis showed that the AGEF score was excellent at predicting clinical outcomes. The optimal cutoff value of the AGEF score for predicting long-term mortality was 2.50 (AUC = 0.743; 95% CI: 0.710-0.776; p < 0.001). Kaplan-Meier survival analysis showed that patients with an AGEF score >2.50 had a worse prognosis than those with an AGEF score ≤2.50 (log-rank χ2 103.69, p < 0.001). Moreover, multivariate Cox proportional hazard analysis showed that an AGEF score ≤2.50 was associated with a lower risk of long-term mortality in elderly patients with NIDCM (HR: 0.405; 95% CI: 0.310-0.529; p < 0.001). CONCLUSIONS: The AGEF score could be considered as a simple and useful tool for risk stratification in elderly patients with NIDCM.

Relationship between serum chloride and prognosis in non-ischaemic dilated cardiomyopathy: a large retrospective cohort study.

OBJECTIVES: Serum chloride has a unique homeostatic role in modulating neurohormonal pathways. Some studies have reported that hypochloremia has potential prognostic value in cardiovascular diseases; thus, we aimed to investigate the association of baseline serum chloride with clinical outcomes in elderly patients with non-ischaemic dilated cardiomyopathy (NIDCM). DESIGN: Retrospective study. SETTING AND PARTICIPANT: A total of 1088 patients (age ≥60 years) diagnosed with NIDCM were enrolled from January 2010 to December 2019. RESULTS: Logistic regression analyses showed that serum chloride was significantly associated with in-hospital death. Receiver operating characteristic (ROC) curve analyses showed that serum chloride had excellent prognostic ability for in-hospital and long-term death (area under the curve (AUC)=0.690 and AUC=0.710, respectively). Kaplan-Meier survival analysis showed that the patients with hypochloremia had worse prognoses than those without hypochloremia (log-rank χ2=56.69, p<0.001). After adjusting for age, serum calcium, serum sodium, left ventricular ejection fraction, lg NT-proBNP and use of diuretics, serum chloride remained an independent predictor of long-term death (HR 0.934, 95% CI 0.913 to 0.954, p<0.001). CONCLUSIONS: Serum chloride concentration was a prognostic indicator in elderly patients with NIDCM, and hypochloremia was significantly associated with both in-hospital and long-term poor outcomes.

Higher dietary acid load is associated with hyperuricemia in Chinese adults: a case-control study.

BACKGROUND: This study aims to explore the association between dietary acid load and hyperuricemia in Chinese adults. METHODS: A case-control study was conducted. Adult participants with hyperuricemia were recruited as the cases and those without hyperuricemia were as the controls. Food consumption was evaluated by food frequency questionnaire (FFQ). Dietary acid load was assessed by potential renal acid load (PRAL) and net endogenous acid production (NEAP). Dietary acid load was divided into four levels: the first quartile (Q1), the second quartile (Q2), the third quartile (Q3) and the fourth quartile (Q4). Logistic regression model was applied for exploring the association between dietary acid load (PRAL and NEAP) and hyperuricemia. Odds ratio (OR) and its correspondence confidence interval (CI) were computed. RESULTS: A total of 290 participants were eligible in this study, in which there were 143 individuals in case group and 147 in control group. A higher level of PRAL was found to be associated with odds of hyperuricemia. ORs of hyperuricemia for Q2, Q3 and Q4 of PRAL were 2.74 (95%CI: 1.94 ~ 3.88, p-value: 0.004), 2.90 (95%CI: 2.05 ~ 4.10, p-value: 0.002) and 3.14 (95%CI: 2.22 ~ 4.45, p-value: 0.001), respectively. There was a positive association between elevated NEAP and hyperuricemia. OR of hyperuricemia for Q2 was not material significance (OR:1.54, 95%CI: 0.93 ~ 2.53, p-value: 0.210), however, ORs of hyperuricemia for Q3 (OR: 2.40, 95%CI: 1.70 ~ 3.38, p-value: 0.011) and Q4 (OR: 3.27, 95%CI: 2.31 ~ 4.62, p-value: 0.001) were statistically significant. CONCLUSION: Higher level of dietary acid load was found to be associated with hyperuricemia in Chinese adults, indicative of advocation of a well-balanced diet in this population.

The Novel LncRNA AK035396 Drives Cardiomyocyte Apoptosis Through Mterf1 in Myocardial Ischemia/Reperfusion Injury.

Background: Myocardial ischaemia/reperfusion (I/R) injury is still a major challenge in clinical treatment. The role of long non-coding RNA (lncRNA) in the regulation of myocardial I/R injury still needs to be elucidated. Methods: The primary isolated neonatal mousse cardiomyocytes and adult mice were used to construct a myocardial ischemia-reperfusion model. qRT-PCR is used to verify gene expression in myocardial tissue and myocardial cells. The effect of AK035396 in primary cardiomyocytes and mouse myocardium was confirmed by TUNEL staining and in vitro flow cytometry experiments. RNA pulldown and Western blot were used to identify AK035396 interacting proteins. The expression of apoptosis-related proteins was identified by qRT-PCR and Western blot. Results: In vivo and in vitro MIRI models, AK035396 was up-regulated after myocardial infarction. Functional studies have shown that knockdown of AK035396 reduces the apoptosis of primary cardiomyocytes and mouse myocardial tissue. AK035396 directly interacts with Mterf1 and inhibits the level of Mterf1. Further experiments have shown that inhibiting Mterf1 will promote the expression of mitochondrial genes COXII and CYTb and cause cell apoptosis. Conclusion: AK035396 plays an important role in myocardial ischaemia-reperfusion injury by regulating the Mterf1-COXII/CYTb pathway.