PEX3 promotes regenerative repair after myocardial injury in mice through facilitating plasma membrane localization of ITGB3.

The peroxisome is a versatile organelle that performs diverse metabolic functions. PEX3, a critical regulator of the peroxisome, participates in various biological processes associated with the peroxisome. Whether PEX3 is involved in peroxisome-related redox homeostasis and myocardial regenerative repair remains elusive. We investigate that cardiomyocyte-specific PEX3 knockout (Pex3-KO) results in an imbalance of redox homeostasis and disrupts the endogenous proliferation/development at different times and spatial locations. Using Pex3-KO mice and myocardium-targeted intervention approaches, the effects of PEX3 on myocardial regenerative repair during both physiological and pathological stages are explored. Mechanistically, lipid metabolomics reveals that PEX3 promotes myocardial regenerative repair by affecting plasmalogen metabolism. Further, we find that PEX3-regulated plasmalogen activates the AKT/GSK3ß signaling pathway via the plasma membrane localization of ITGB3. Our study indicates that PEX3 may represent a novel therapeutic target for myocardial regenerative repair following injury.

Checkpoint Kinase 1 Stimulates Endogenous Cardiomyocyte Renewal and Cardiac Repair by Binding to Pyruvate Kinase Isoform M2 C-Domain and Activating Cardiac Metabolic Reprogramming in a Porcine Model of Myocardial Ischemia/Reperfusion Injury.

BACKGROUND: The regenerative capacity of the adult mammalian hearts is limited. Numerous studies have explored mechanisms of adult cardiomyocyte cell-cycle withdrawal. This translational study evaluated the effects and underlying mechanism of rhCHK1 (recombinant human checkpoint kinase 1) on the survival and proliferation of cardiomyocyte and myocardial repair after ischemia/reperfusion injury in swine. METHODS AND RESULTS: Intramyocardial injection of rhCHK1 protein (1 mg/kg) encapsulated in hydrogel stimulated cardiomyocyte proliferation and reduced cardiac inflammation response at 3 days after ischemia/reperfusion injury, improved cardiac function and attenuated ventricular remodeling, and reduced the infarct area at 28 days after ischemia/reperfusion injury. Mechanistically, multiomics sequencing analysis demonstrated enrichment of glycolysis and mTOR (mammalian target of rapamycin) pathways after rhCHK1 treatment. Co-Immunoprecipitation (Co-IP) experiments and protein docking prediction showed that CHK1 (checkpoint kinase 1) directly bound to and activated the Serine 37 (S37) and Tyrosine 105 (Y105) sites of PKM2 (pyruvate kinase isoform M2) to promote metabolic reprogramming. We further constructed plasmids that knocked out different CHK1 and PKM2 amino acid domains and transfected them into Human Embryonic Kidney 293T (HEK293T) cells for CO-IP experiments. Results showed that the 1-265 domain of CHK1 directly binds to the 157-400 amino acids of PKM2. Furthermore, hiPSC-CM (human iPS cell-derived cardiomyocyte) in vitro and in vivo experiments both demonstrated that CHK1 stimulated cardiomyocytes renewal and cardiac repair by activating PKM2 C-domain-mediated cardiac metabolic reprogramming. CONCLUSIONS: This study demonstrates that the 1-265 amino acid domain of CHK1 binds to the 157-400 domain of PKM2 and activates PKM2-mediated metabolic reprogramming to promote cardiomyocyte proliferation and myocardial repair after ischemia/reperfusion injury in adult pigs.

Association between urinary cadmium level and subclinical myocardial injury in the general population without cardiovascular disease aged ≥ 50 years.

Cadmium (Cd) is a toxic heavy metal linked to an increased risk of cardiovascular disease (CVD). But the relationship between urinary Cd (U-Cd) and electrocardiographic subclinical myocardial injury (SC-MI) in older people is unclear. This study evaluated the connection between U-Cd and SC-MI in people who did not have CVD. The study involved 4269 participants from the National Health and Nutrition Examination Survey III(NHANES III) aged ≥ 50 years and had no history of CVD. The relationship between U-Cd and cardiac infarction/injury score (CIIS) was assessed by multivariable linear regression. Whether U-Cd and SC-MI were correlated was determined by multivariate logistic regression, restricted cubic spline, and subgroup analysis. There was a significant association between U-Cd and CIIS (ß, 1.04, 95% confidence interval (CI): 0.39-1.69; P = 0.003) in the highest quartile and fully adjusted model. After adjusting for relevant confounders, multivariable logistic regression showed that participants in the highest quartile of U-Cd had a greater chance of having SC-MI than those in the first ( OR (95% CI), 1.37(1.13,1.66), P for trend = 0.003), and this relationship was especially strong among hypertensive participants. And a positive linear correlation between U-Cd and the prevalence of SC-MI was shown by restricted cubic spline analysis. U-Cd may be a novel risk element for SC-MI because it is independently and linearly linked to CIIS and SC-MI.

Association of glycation gap with all-cause and cardiovascular mortality in US adults: A nationwide cohort study.

AIM: To investigate the relationship of the glycation gap (GGap) with all-cause and cardiovascular (CV) mortality in US adults. METHODS: This was a retrospective cohort study comprising 12 909 individual participant data from the National Health and Nutrition Examination Survey from 1999 to 2004 and their mortality data through 31 December 2019. Weighted Cox proportional hazards regression models and restricted cubic splines were used to investigate the associations between GGap and mortality. RESULTS: During a median follow-up of 16.8 years, 3528 deaths occurred, including 1140 CV deaths. The associations of GGap with risk of all-cause and CV mortality were U-shaped (both P for non-linearity < .001). Compared with individuals with a GGap of 0.09%-0.38% (61st-80th centiles), the multivariable-adjusted HRs and 95% CIs for individuals with a GGap less than -0.83% (first-fifth centiles) and individuals with a GGap greater than 0.90% (96th-100th centiles) were 1.36 (1.10, 1.69) and 1.21 (1.00, 1.45) for all-cause mortality, and 1.77 (1.16, 2.71) and 1.43 (1.04, 1.95) for CV mortality. The GGap value associated with the lowest risk of all-cause and CV mortality was 0.38% in the general population and 0.78% among individuals with diabetes. CONCLUSIONS: We found a U-shaped association between GGap and all-cause and CV mortality, with significant positive or negative GGap values associated with increased mortality risk, probably because of glycaemic variability and fructosamine-3-kinase activity.

Improved methodology for efficient establishment of the myocardial ischemia-reperfusion model in pigs through the median thoracic incision.

To investigate the feasibility and effectiveness of establishing porcine ischemia-reperfusion models by ligating the left anterior descending (LAD) coronary artery, we first randomly divided 16 male Bama pigs into a sham group and a model group. After anesthesia, we separated the arteries and veins. Subsequently, we rapidly located the LAD coronary artery at the beginning of its first diagonal branch through a mid-chest incision. Then, we loosened and released the ligation line after five minutes of pre-occlusion. Finally, we ligated the LAD coronary artery in situ two minutes later and loosened the ligature 60 min after ischemia. Compared with the sham group, electrocardiogram showed multiple continuous lead ST-segment elevations, and ultrasound cardiogram showed significantly lower ejection fraction and left ventricular fractional shortening at one hour and seven days post-operation in the model group. Twenty-four hours after the operation, cardiac troponin T and creatine kinase-MB isoenzyme levels significantly increased in the model group, compared with the sham group. Hematoxylin and eosin staining showed the presence of many inflammatory cells infiltrating the interstitium of the myocardium in the model group but not in the sham group. Masson staining revealed a significant increase in infarct size in the ischemia/reperfusion group. All eight pigs in the model group recovered with normal sinus heart rates, and the survival rate was 100%. In conclusion, the method can provide an accurate and stable large animal model for preclinical research on ischemia/reperfusion with a high success rate and homogeneity of the myocardial infarction area.

P16INK4a Regulates ROS-Related Autophagy and CDK4/6-Mediated Proliferation: A New Target of Myocardial Regeneration Therapy.

Neonatal mice achieve complete cardiac repair through endogenous myocardial regeneration after apical resection (AR), but this capacity is rapidly lost 7 days after birth. As an upstream inhibitor of cyclin-dependent kinase 4/6- (CDK4/6-) mediated cell cycle activity, p16INK4a is widely involved in regulating tumor and senescence. Given that p16INK4a had a significant negative regulation on cell proliferation, targeting cardiomyocytes (CMs) to inhibit p16INK4a seems to be a promising attempt at myocardial regeneration therapy. The p16INK4a expression was upregulated during perimyocardial regeneration time. Knockdown of p16INK4a stimulated CM proliferation, while p16INK4a overexpression had the opposite effect. In addition, p16INK4a knockdown prolonged the proliferation time window of newborn myocardium. And p16INK4a overexpression inhibited cell cycle activity and deteriorated myocardial regeneration after AR. The quantitative proteomic analysis showed that p16INK4a knockdown mediated the cell cycle progression and intervened in energy metabolism homeostasis. Mechanistically, overexpression of p16INK4a causes abnormal accumulation of reactive oxygen species (ROS) to induce autophagy, while scavenging ROS with N-acetylcysteine can alleviate autophagy and regulate p16INK4a, CDK4/6, and CyclinD1 in a covering manner. And the effect of inhibiting the proliferation of p16INK4a-activated CMs was significantly blocked by the CDK4/6 inhibitor Palbociclib. In summary, p16INK4a regulated CM proliferation progression through CDK4/6 and ROS-related autophagy to jointly affect myocardial regeneration repair. Our study revealed that p16INK4a might be a potential therapeutic target for myocardial regeneration after injury.

Association of serum osmolality with all-cause and cardiovascular mortality in US adults: A prospective cohort study.

BACKGROUND AND AIMS: The association between serum osmolality, an effective indicator of body hydration status, and long-term mortality in the general population remains undetermined. The present study aimed to investigate the association of serum osmolality with long-term all-cause and cardiovascular mortality among adults in the United States. METHODS AND RESULTS: This cohort study used data from the National Health and Nutrition Examination Survey (NHANES) 2007-2014. Participants were linked to National Death Index mortality data from the survey date through December 31, 2019. Cox proportional hazards regression model was used to calculate hazard ratios (HRs) and 95% CIs, and restricted cubic spline (RCS) regression was conducted. A total of 18312 US adults were included. During a median follow-up of 8.7 years, 1353 total deaths occurred, including 379 cardiovascular deaths. After multivariable adjustments, compared with the 3rd quartile (Q3) of serum osmolality, participants in the 1st (Q1) and 4th (Q4) quartiles were at a significantly higher risk of all-cause mortality (HR 1.41 [95% CI, 1.14-1.75] and 1.29 [95% CI, 1.04-1.61], respectively). RCS revealed a nonlinear relationship of serum osmolality to all-cause and cardiovascular mortality, with an inflection point of 278 mmol/kg. CONCLUSION: In the nationally representative cohort of US adults, serum osmolality was nonlinearly associated with all-cause and cardiovascular mortality. The risk of mortality was lowest around an osmolality of 278 mmol/kg. These findings suggest the importance of serum osmolality management for long-term health outcomes.

Combination of D-dimer level and neutrophil to lymphocyte ratio predicts long-term clinical outcomes in acute coronary syndrome after percutaneous coronary intervention.

BACKGROUND: High D-dimer (DD) is associated with short-term adverse outcomes in patients with acute coronary syndrome (ACS). In ACS patients who underwent percutaneous coronary intervention (PCI), however, the value of DD (or combined with neutrophil to lymphocyte ratio [NLR]) to predict long-term major adverse cardiovascular events (MACEs) has not been fully evaluated. METHODS: Patients diagnosed with ACS and receiving PCI were included. The primary outcome was MACEs. Cox proportional hazards regression and logistic regression were used to illustrate the relationship between clinical risk factors, biomarkers and MACEs. Survival models were developed based on significant factors and evaluated by the Concordance-index (C-index). RESULTS: The final study cohort was comprised of 650 patients (median age, 64 years; 474 males), including 98 (15%) with MACEs during a median follow-up period of 40 months. According to the cut-off value of DD and NLR, the patients were separated into four groups: high DD or nonhigh DD with high or nonhigh NLR. After adjusting for confounding variables, DD (adjusted hazard ratio [aHR]: 2.39, 95% confidence interval [CI]: 1.52-3.76) and NLR (aHR: 2.71, 95% CI: 1.78-4.11) were independently associated with long-term MACEs. Moreover, patients with both high DD and NLR had a significantly higher risk in MACEs when considering patients with nonhigh DD and NLR as reference (aHR: 6.19, 95% CI: 3.30-11.61). The area under curve increased and reached 0.70 in differentiating long-term MACEs when DD and NLR were combined, and survival models incorporating the two exhibited a stronger predictive power (C-index: 0.75). CONCLUSIONS: D-dimer (or combined with NLR) can be used to predict long-term MACEs in ACS patients undergoing PCI.

Mediation Effect of Body Mass Index on the Association of Urinary Nickel Exposure with Serum Lipid Profiles.

The objective of this study was to determine the relationship of urinary nickel (U-Ni) exposure to serum lipid profiles and the mediation effect of body mass index (BMI) in a US general population. We analyzed the cross-sectional data from 3517 participants in the National Health and Nutrition Examination Survey (NHANES) (2017-March 2020). Multivariable linear regression and restricted cubic spline (RCS) regression were conducted to explore the association of U-Ni with four serum lipids and four lipids-derived indicators. Mediation analysis was performed to examine the effect of BMI on the relationship between U-Ni levels and serum lipid profiles. Compared with the lowest quartile, the ß with 95% confidence intervals (CIs) in the highest quartile were - 12.83 (- 19.42, - 6.25) for total cholesterol (TC) (P for trend < 0.001), - 12.76 (- 19.78, - 5.74) for non-high-density lipoprotein cholesterol (non-HDL-C) (P for trend = 0.001) and - 0.29 (- 0.51, - 0.07) for TC/HDL-C (P for trend = 0.007) in the fully adjusted model. RCS plots showed the linear association of log2-transformed U-Ni levels with TC, non-HDL-C and TC/HDL-C (P for nonlinearity = 0.294, 0.152, and 0.087, respectively). Besides, BMI decreased monotonically in correlation with increasing U-Ni levels (P for trend < 0.001). Mediation analysis revealed that BMI significantly mediated the relationship of U-Ni to TC, non-HDL-C and TC/HDL-C with mediated proportions of 11.17%, 22.20% and 36.44%, respectively. In summary, our findings suggest that BMI mediates the negative association of U-Ni with TC, non-HDL-C, and TC/HDL-C in the US general population.

Association of Urinary Strontium with Cardiovascular Disease Among the US Adults: A Cross-Sectional Analysis of the National Health and Nutrition Examination Survey.

Previous studies have demonstrated the effects of environmental metals on the cardiovascular system. However, the relationship of strontium (Sr) to cardiovascular disease (CVD) in the general population has not been established. This cross-sectional study aimed to investigate the association between urinary Sr (U-Sr) and CVD in the US adults using data of 5255 participants from the National Health and Nutrition Examination Survey (NHANES) 2011-2016. Multivariable logistic regression and restricted cubic spline (RCS) regression were performed to assess the association between U-Sr and CVD. After multivariable adjustments, compared to the lowest quartile, the adjusted odds ratios (ORs) of CVD with 95% confidence intervals (CIs) across the quartiles were 0.65 (0.46, 0.92), 0.87 (0.61, 1.25), and 0.78 (0.55, 1.10). RCS plot revealed a nonlinear relationship between U-Sr levels and CVD (P for nonlinearity = 0.004). Threshold effect analysis identified the inflection point of U-Sr for the curve was 90.18 µg/g urinary creatinine (µg/g UCr). Each 1-unit increase in U-Sr was associated with a 1.1% decrease in CVD (OR 0.989; 95% CI 0.980-0.998) on the left side of the inflection point, but no significant association was observed on the right side of the inflection point. This study suggests a nonlinear association of U-Sr with CVD prevalence in the US general adults. These findings may have positive implications for the determination of appropriate Sr levels for public cardiovascular health. Given the cross-sectional study design, further prospective studies are warranted.

Integrated transcriptomic and proteomic analysis reveals potential targets for heart regeneration.

Research on the regenerative capacity of the neonatal heart could open new avenues for the treatment of myocardial infarction (MI). However, the mechanism of cardiac regeneration remains unclear. In the present study, we constructed a mouse model of heart regeneration and then performed transcriptomic and proteomic analyses on them. Gene Ontology (GO) enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, and Gene Set Enrichment Analysis (GSEA) of differentially expressed genes (DEGs) were conducted. Western blot (WB) and qPCR analyses were used to validate the hub genes expression. As a result, gene expression at the mRNA level and protein level is not the same. We identified 3186 DEGs and 42 differentially expressed proteins (DEPs). Through functional analysis of DEGs and DEPs, we speculate that biological processes such as ubiquitination, cell cycle, and oxygen metabolism are involved in heart regeneration. Integrated transcriptomic and proteomic analysis identified 19 hub genes and Ankrd1, Gpx3, and Trim72 were screened out as potential regulators of cardiac regeneration through further expression verification. In conclusion, we combined transcriptomic and proteomic analyses to characterize the molecular features during heart regeneration in neonatal mice. Finally, Ankrd1, Gpx3, and Trim72 were identified as potential targets for heart regeneration therapy.

Association of glycated albumin to hemoglobin A1c ratio with all-cause and cardiovascular mortality among US adults: A population-based cohort study.

AIMS: To investigate the association of glycated albumin to hemoglobin A1c (GA/HbA1c) ratio, an indicator of blood glucose fluctuations, with all-cause and cardiovascular mortality among US adults. METHODS: This cohort study used data from the National Health and Nutrition Examination Survey 1999-2004. Participants were linked to National Death Index mortality data through December 31, 2015. Cox proportional hazards model was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs), and restricted cubic spline (RCS) regression was conducted. RESULTS: A total of 11,508 US adults (weighted mean age, 43.9 years; 5748 males [weighted, 48.9 %]) were included. During a median follow­up of 13.6 years, 1963 total deaths occurred, including 383 cardiovascular deaths. After multivariable adjustments, a higher GA/HbA1c ratio was associated with a higher risk of all-cause (tertiles: P for trend < 0.001; continuous: HR 1.49 [95 % CI 1.32-1.69]) and cardiovascular (tertiles: P for trend = 0.048; continuous: HR 1.65 [95 % CI 1.27-2.14]) mortality. RCS revealed a linear relationship of GA/HbA1c ratio to mortality. CONCLUSIONS: In the nationally representative cohort of US adults, GA/HbA1c ratio was significantly associated with the risk of all-cause and cardiovascular mortality. These findings suggest that GA/HbA1c ratio may serve as an effective indicator for identifying high-risk individuals.

CDK9 binds and activates SGK3 to promote cardiac repair after injury via the GSK-3ß/ß-catenin pathway.

The mammalian heart possesses entire regeneration capacity after birth, which is lost in adulthood. The role of the kinase network in myocardial regeneration remains largely elusive. SGK3 (threonine-protein kinase 3) is a functional kinase we identified previously with the capacity to promote cardiomyocyte proliferation and cardiac repair after myocardial infarction. However, the upstream signals regulating SGK3 are still unknown. Based on the quantitative phosphoproteomics data and pulldown assay, we identified cyclin-dependent kinase 9 (CDK9) as a novel therapeutic target in regeneration therapy. The direct combination between CDK9 and SGK3 was further confirmed by co-immunoprecipitation (Co-IP). CDK9 is highly expressed in the newborn period and rarely detected in the adult myocardium. In vitro, the proliferation ratio of primary cardiomyocytes was significantly elevated by CDK9 overexpression while inhibited by CDK9 knockdown. In vivo, inhibition of CDK9 shortened the time window of cardiac regeneration after apical resection (AR) in neonatal mice, while overexpression of CDK9 significantly promoted mature cardiomyocytes (CMs) to re-enter the cell cycle and cardiac repair after myocardial infarction (MI) in adult mice. Mechanistically, CDK9 promoted cardiac repair by directly activating SGK3 and downstream GSK-3ß/ß-catenin pathway. Consequently, our study indicated that CDK9 might be a novel target for MI therapy by stimulating myocardial regeneration.

Association of hemoglobin glycation index and glycation gap with cardiovascular disease among US adults.

AIMS: To investigate the association of hemoglobin glycation index (HGI) and glycation gap (GGap), reflecting mismatches between HbA1c and other measures of glycemia, with cardiovascular disease (CVD) in the general population. METHODS: 5966 US adult (age ≥ 20 years) participants were included from the National Health and Nutrition Examination Survey (NHANES) (1999-2004). In this cross-sectional study, predicted HbA1c was calculated based on fasting plasma glucose (FPG) and glycated albumin (GA), respectively. Multivariable binary logistic regression analysis was performed to explore the association of HGI and GGap with CVD prevalence. RESULTS: Compared to the lowest tertile, the ORs with 95% CIs for CVD across the tertiles were 1.41 (1.01, 1.96) and 0.87 (0.58, 1.31) for HGI (P for trend = 0.535) and 1.06 (0.77, 1.47) and 1.60 (1.18, 2.17) for GGap (P for trend = 0.002) in the fully-adjusted model. Besides, the discordantly high GGap/low HbA1c group was associated with higher CVD prevalence compared with the low GGap/high HbA1c group (OR = 1.50, 95% CI, 1.04-2.16, P = 0.030). CONCLUSIONS: GGap derived from GA is associated with CVD independent of traditional risk factors, even HbA1c, in US general adults. Considering the potential limitations of HbA1c, the introduction of GGap is warranted.

LncRNA FAF attenuates hypoxia/ischaemia-induced pyroptosis via the miR-185-5p/PAK2 axis in cardiomyocytes.

Pyroptosis is associated with various cardiovascular diseases. Increasing evidence suggests that long noncoding RNAs (lncRNAs) have been implicated in gene regulation, but how lncRNAs participate in the regulation of pyroptosis in the heart remains largely unknown. In this study, we aimed to explore the antipyroptotic effects of lncRNA FGF9-associated factor (FAF) in acute myocardial infarction (AMI). The expression patterns of lncRNA FAF, miR-185-5p and P21 activated kinase 2 (PAK2) were detected in hypoxia/ischaemia-induced cardiomyocytes. Hoechst 33342/PI staining, lactate dehydrogenase (LDH) release assay, immunofluorescence and Western blotting were conducted to assay cell pyroptosis. The interaction between lncRNA FAF, miR-185-5p and PAK2 was verified by bioinformatics analysis, small RNA sequencing luciferase reporter assay and qRT-PCR. The expression of LncRNA FAF was downregulated in hypoxic cardiomyocytes and myocardial tissues. Overexpression of lncRNA FAF could attenuate cardiomyocyte pyroptosis, improve cell viability and reduce infarct size during the procession of AMI. Moreover, lncRNA FAF was confirmed as a sponge of miR-185-5p and promoted PAK2 expression in cardiomyocytes. Collectively, our findings reveal a novel lncRNA FAF/miR-185-5p/PAK2 axis as a crucial regulator in cardiomyocyte pyroptosis, which might be a potential therapeutic target of AMI.

MNK2-eIF4E axis promotes cardiac repair in the infarcted mouse heart by activating cyclin D1.

Adult mammals have limited potential for cardiac regeneration after injury. In contrast, neonatal mouse heart, up to 7 days post birth, can completely regenerate after injury. Therefore, identifying the key factors promoting the proliferation of endogenous cardiomyocytes (CMs) is a critical step in the development of cardiac regeneration therapies. In our previous study, we predicted that mitogen-activated protein kinase (MAPK) interacting serine/threonine-protein kinase 2 (MNK2) has the potential of promoting regeneration by using phosphoproteomics and iGPS algorithm. Here, we aimed to clarify the role of MNK2 in cardiac regeneration and explore the underlying mechanism. In vitro, MNK2 overexpression promoted, and MNK2 knockdown suppressed cardiomyocyte proliferation. In vivo, inhibition of MNK2 in CMs impaired myocardial regeneration in neonatal mice. In adult myocardial infarcted mice, MNK2 overexpression in CMs in the infarct border zone activated cardiomyocyte proliferation and improved cardiac repair. In CMs, MNK2 binded to eIF4E and regulated its phosphorylation level. Knockdown of eukaryotic translation initiation factor (eIF4E) impaired the proliferation-promoting effect of MNK2 in CMs. MNK2-eIF4E axis stimulated CMs proliferation by activating cyclin D1. Our study demonstrated that MNK2 kinase played a critical role in cardiac regeneration. Over-expression of MNK2 promoted cardiomyocyte proliferation in vitro and in vivo, at least partly, by activating the eIF4E-cyclin D1 axis. This investigation identified a novel target for heart regenerative therapy.

Association between urinary thallium exposure and cardiovascular disease in U.S. adult population.

Exposure to environmental metals, especially heavy metals, can damage human health. However, the association between metals and the prevalence of cardiovascular disease (CVD) remains controversial. The objective of this study was to determine the relationship of urinary metals to CVD in a general population of U.S. adults. We analyzed the cross-sectional data from 6867 adult (age ≥20 years) participants with 12 urinary metals in the National Health and Nutrition Examination Survey (NHANES) (2011-2016). Multivariate logistic regression and restricted cubic spline (RCS) regression were conducted to explore the association between urinary metals and CVD outcomes. Sensitivity analyses were performed to test the robustness of the results. Compared to the lowest quartile, the odds ratios with 95% confidence intervals for CVD across the quartiles were 0.73 (0.38, 1.42), 0.58 (0.42, 0.81), and 0.71 (0.59, 0.84) for urinary thallium (U-Tl) (P for trend <0.001). RCS plot showed the nonlinear association between log2-transformed U-Tl levels and CVD (P for nonlinearity = 0.001). Sensitivity analyses confirmed the robustness. Higher concentrations of urinary cobalt, manganese and tungsten were associated with an increased risk of CVD. In summary, the large sample data suggests U-Tl is nonlinearly and negatively associated with the prevalence of CVD in the U.S. general adults with low exposure levels. Considering the shortcomings of cross-sectional study design, further studies are warranted to verify our results and to clarify the potential mechanisms.

P16ink4a overexpression ameliorates cardiac remodeling of mouse following myocardial infarction via CDK4/pRb pathway.

BACKGROUND: P16ink4a can accumulate in senescent cells and can be induced by different oncogenic stimulations. These functions make p16ink4a a biomarker of senescence and cancer. However, the exact role of p16ink4a remains unclear in cardiovascular disease. This study was aimed to investigate the role of p16ink4a in cardiac remodeling after myocardial infarction (MI). METHODS: In vivo, gain and loss of function experiments using p16ink4a overexpression and knockdown adenovirus were induced to determine the effect of p16ink4a on cardiac structure and function after MI. The in vitro effects of p16ink4a were evaluated by overexpression and knockdown adenovirus of p16ink4a on isolated neonatal mouse cardiac myocytes (NMCMs) and neonatal mouse cardiac fibroblasts (NMCFs). RESULTS: Expression level of p16ink4a was increased after MI and enriched in the infarction area. In vivo, overexpression of p16ink4a protected, while knockdown of p16ink4a worsened cardiac function. In vitro, p16ink4a did not influence the hypertrophy of NMCMs. Overexpression of p16ink4a inhibited the proliferation and migration of NMCFs and reduced the level of collagen I and α-SMA. Consistently, knockdown of p16ink4a in vitro displayed the opposite effects. Further mechanism studies revealed that p16ink4a affected the expression level of cyclin-dependent kinase 4 (CDK4) and phosphorylation of retinoblastoma (pRb), which could be a potential pathway in regulating cardiac remodeling after MI. CONCLUSION: Overexpression of 16ink4a in cardiac fibroblasts can ameliorate cardiac dysfunction and attenuate pathological cardiac remodeling in mice after MI by regulating the p16ink4a/CDK4/pRb pathway.

Programmed Cell Death: Complex Regulatory Networks in Cardiovascular Disease.

Abnormalities in programmed cell death (PCD) signaling cascades can be observed in the development and progression of various cardiovascular diseases, such as apoptosis, necrosis, pyroptosis, ferroptosis, and cell death associated with autophagy. Aberrant activation of PCD pathways is a common feature leading to excessive cardiac remodeling and heart failure, involved in the pathogenesis of various cardiovascular diseases. Conversely, timely activation of PCD remodels cardiac structure and function after injury in a spatially or temporally restricted manner and corrects cardiac development similarly. As many cardiovascular diseases exhibit abnormalities in PCD pathways, drugs that can inhibit or modulate PCD may be critical in future therapeutic strategies. In this review, we briefly describe the process of various types of PCD and their roles in the occurrence and development of cardiovascular diseases. We also discuss the interplay between different cell death signaling cascades and summarize pharmaceutical agents targeting key players in cell death signaling pathways that have progressed to clinical trials. Ultimately a better understanding of PCD involved in cardiovascular diseases may lead to new avenues for therapy.