Proline metabolic reprogramming modulates cardiac remodeling induced by pressure overload in the heart.

Metabolic reprogramming is critical in the onset of pressure overload-induced cardiac remodeling. Our study reveals that proline dehydrogenase (PRODH), the key enzyme in proline metabolism, reprograms cardiomyocyte metabolism to protect against cardiac remodeling. We induced cardiac remodeling using transverse aortic constriction (TAC) in both cardiac-specific PRODH knockout and overexpression mice. Our results indicate that PRODH expression is suppressed after TAC. Cardiac-specific PRODH knockout mice exhibited worsened cardiac dysfunction, while mice with PRODH overexpression demonstrated a protective effect. In addition, we simulated cardiomyocyte hypertrophy in vitro using neonatal rat ventricular myocytes treated with phenylephrine. Through RNA sequencing, metabolomics, and metabolic flux analysis, we elucidated that PRODH overexpression in cardiomyocytes redirects proline catabolism to replenish tricarboxylic acid cycle intermediates, enhance energy production, and restore glutathione redox balance. Our findings suggest PRODH as a modulator of cardiac bioenergetics and redox homeostasis during cardiac remodeling induced by pressure overload. This highlights the potential of PRODH as a therapeutic target for cardiac remodeling.

Aiming at early-stage vulnerable plaques: A nanoplatform with dual-mode imaging and lipid-inflammation integrated regulation for atherosclerotic theranostics.

The vulnerable plaques in atherosclerosis can cause severe outcome with great danger of acute cardiovascular events. Thus, timely diagnosis and treatment of vulnerable plaques in early stage can effectively benefit the clinical management of atherosclerosis. In this work, a targeting theranostic strategy on early-stage vulnerable plaques in atherosclerosis is realized by a LAID nanoplatform with X-CT and fluorescent dual-mode imaging and lipid-inflammation integrated regulation abilities. The iodinated contrast agents (ICA), phenylboronic acid modified astaxanthin and oxidized-dextran (oxDEX) jointly construct the nanoparticles loaded with the lipid-specific probe LFP. LAID indicates an active targeting to plaques along with the dual-responsive disassembly in oxidative stress and acidic microenvironment of atherosclerosis. The X-CT signals of ICA execute the location of early-stage plaques, while the LFP combines with lipid cores and realizes the recognition of vulnerable plaques. Meanwhile, the treatment based on astaxanthin is performed for restraining the progression of plaques. Transcriptome sequencing suggests that LAID can inhibit the lipid uptake and block NF-κB pathway, which synergistically demonstrates a lipid-inflammation integrated regulation to suppression the plaques growing. The in vivo investigations suggest that LAID delivers a favorable theranostics to the early-stage vulnerable plaques, which provides an impressive prospect for reducing the adverse prognosis of atherosclerosis.

Targeting Nanoplatform for Atherosclerosis Inhibition and Degradation via a Dual-Track Reverse Cholesterol Transport Strategy.

As a main cause of serious cardiovascular diseases, atherosclerosis is characterized by deposited lipid and cholesterol crystals (CCs), which is considered as a great challenge to the current treatments. In this study, a dual-track reverse cholesterol transport strategy is used to overcome the cumulative CCs in the atherosclerotic lesions via a targeting nanoplatform named as LPLCH. Endowed with the active targeting ability to the plaques, the nanoparticles can be efficiently internalized and achieve a pH-triggered charge conversion for the escape from lysosomes. During this procedure, the liver X receptor (LXR) agonists loaded in nanoparticles are replaced by the deposited lysosomal CCs, leading to a LXR mediated up-regulation of ATP-binding cassette transporte ABCA1/G1 with the local CCs carrying at the same time. Thus, the cumulative CCs are removed in a dual-track way of ABCA1/G1 mediated efflux and nanoparticle-based carrying. The in vivo investigations indicate that LPLCH exhibits a favorable inhibition on the plaque progression and a further reversal of formed lesions when under a healthy diet. And the RNA-sequencing suggests that the cholesterol transport also synergistically activates the anti-inflammation effect. The dual-track reverse cholesterol transport strategy performed by LPLCH delivers an exciting candidate for the effective inhibition and degradation of atherosclerosis.

Association between fasting stress hyperglycemia ratio and contrast-induced acute kidney injury in coronary angiography patients: a cross-sectional study.

Aims: Stress hyperglycemia ratio (SHR), an emerging indicator of critical illness, exhibits a significant association with adverse cardiovascular outcomes. The primary aim of this research endeavor is to evaluate the association between fasting SHR and contrast-induced acute kidney injury (CI-AKI). Methods: This cross-sectional study comprised 3,137 patients who underwent coronary angiography (CAG) or percutaneous coronary intervention (PCI). The calculation of fasting SHR involved dividing the admission fasting blood glucose by the estimated mean glucose obtained from glycosylated hemoglobin. CI-AKI was assessed based on elevated serum creatinine (Scr) levels. To investigate the relationship between fasting SHR and the proportion of SCr elevation, piecewise linear regression analysis was conducted. Modified Poisson's regression analysis was implemented to evaluate the correlation between fasting SHR and CI-AKI. Subgroup analysis and sensitivity analysis were conducted to explore result stability. Results: Among the total population, 482 (15.4%) patients experienced CI-AKI. Piecewise linear regression analysis revealed significant associations between the proportion of SCr elevation and fasting SHR on both sides (≤ 0.8 and > 0.8) [ß = -12.651, 95% CI (-23.281 to -2.022), P = 0.020; ß = 8.274, 95% CI (4.176 to 12.372), P < 0.001]. The Modified Poisson's regression analysis demonstrated a statistically significant correlation between both the lowest and highest levels of fasting SHR and an increased incidence of CI-AKI [(SHR < 0.7 vs. 0.7 ≤ SHR < 0.9) ß = 1.828, 95% CI (1.345 to 2.486), P < 0.001; (SHR ≥ 1.3 vs. 0.7 ≤ SHR < 0.9) ß = 2.896, 95% CI (2.087 to 4.019), P < 0.001], which was further validated through subgroup and sensitivity analyses. Conclusion: In populations undergoing CAG or PCI, both lowest and highest levels of fasting SHR were significantly associated with an increased occurrence of CI-AKI.

Polydopamine (PDA) coatings with endothelial vascular growth factor (VEGF) immobilization inhibiting neointimal formation post zinc (zn) wire implantation in rat aortas.

BACKGROUND: Bioresorbable stents are designed to provide temporary mechanical support to the coronary arteries and then slowly degrade in vivo to avoid chronic inflammation. Zinc (Zn) is a promising material for bioresorbable stents; However, it can cause inflammation and neointimal formation after being implanted into blood vessels. METHODS: To improve biocompatibility of Zn, we first coated it with polydopamine (PDA), followed by immobilization of endothelial vascular growth factor (VEGF) onto the PDA coatings. Adhesion, proliferation, and phenotype maintenance of endothelial cells (ECs) on the coated Zn were evaluated in vitro. Then, a wire aortic implantation model in rats mimicking endovascular stent implantation in humans was used to assess vascular responses to the coated Zn wires in vivo. Thrombosis in aortas post Zn wire implantation, degradation of Zn wires in vivo, neointimal formation surrounding Zn wires, and macrophage infiltration and extracellular matrix (ECM) remodeling in the neointimas were examined. RESULTS: In vitro data showed that the PDA-coated Zn encouraged EC adhesion, spreading, proliferation, and phenotype maintenance on its surfaces. VEGF functionalization on PDA coatings further enhanced the biocompatibility of Zn to ECs. Implantation of PDA-coated Zn wires into rat aortas didn't cause thrombosis and showed a faster blood flow than pure Zn or the Zn wires coated with VEGF alone. In addition, the PDA coating didn't affect the degradation of Zn wires in vivo. Besides, the PDA-coated Zn wires reduced neointimal formation, increased EC coverage, decreased macrophage infiltration, and declined aggrecan accumulation in ECM. VEGF immobilization onto PDA coatings didn't cause thrombosis and affect Zn degradation in vivo as well, and further increased the endothelization percentage as compared to PDA coating alone, thus resulting in thinner neointimas. CONCLUSION: These results indicate that PDA coatings with VEGF immobilization would be a promising approach to functionalize Zn surfaces to increase biocompatibility, reduce inflammation, and inhibit neointimal formation after Zn implantation in vivo.

Biomimetic and NOS-Responsive Nanomotor Deeply Delivery a Combination of MSC-EV and Mitochondrial ROS Scavenger and Promote Heart Repair and Regeneration.

Mesenchymal stem cell-derived extracellular vesicle (MSC-EV) is shown to promote cardiac repair, however, it still falls short in initiating myocardia proliferation restart. In this regard, ROS-induced DNA damage and responses are the culprit of cellcycle arrest. Here, this work constructs a hybrid cell-derived extracellular vesicle that is composed of MSC and macrophage membranes and encompasses MitoN, a ROS scavenger, to boost the healing of the heart. The MitoN, a NAD(P)H mimic, could target the mitochondrial to eliminate the ROS resuming the arrested cell cycle. The hybrid extracellular vesicle (N@MEV) could respond to the inflammatory signals generated during myocardial injury and thus enable superior targeting and enrichment to the location of the damage. L-arginine, which could be catalyzed by NOS and ROS into NO and SO provide a driving force, is immobilized within the vesicle (NA@MEV) to further enhance the N@MEV's potential to penetrate the cardiac stroma. In combination with multiple mechanisms, NA@MEV increased heart function 1.3-fold EF% versus MSC-EV in mouse myocardial injury model. A more in-depth mechanistic study found that the NA@MEV could modulate M2 macrophage; promote angiogenesis; reduce DNA damage and response, and thereby restart cardiomyocyte proliferation. Thus, this combined therapy shows synthetic effects in heart repair and regeneration.

Palmitic Acid, A Critical Metabolite, Aggravates Cellular Senescence Through Reactive Oxygen Species Generation in Kawasaki Disease.

Coronary artery lesions (CALs) are severe complications of Kawasaki disease (KD), resulting in stenosis and thrombogenesis. Metabolomic profiling of patients' plasma could assist in elucidating the pathogenesis of CALs and identifying diagnostic biomarkers, which are imperative for clinical treatment. The metabolic profiles between KD patients with CALs and without CALs (non-coronary artery lesion, or NCAL, group) indicated the most significantly differentially expressed metabolite, palmitic acid (PA), showed the most massive fold change at 9.879. Furthermore, PA was proven to aggravate endothelial cellular senescence by increasing the generation of reactive oxygen species (ROS) in KD, and those two phenotypes were confirmed to be enriched among the differentially expressed genes between KD and normal samples from GEO datasets. Collectively, our findings indicate that cellular senescence may be one of the mechanisms of vascular endothelial damage in KD. PA may be a biomarker and potential therapeutic target for predicting the occurrence of CALs in KD patients. All things considered, our findings confirm that plasma metabolomics was able to identify promising biomarkers and potential pathogenesis mechanisms in KD. To conclude, Palmitic acid could be a novel target in future studies of CALs in patients with KD.

Docosahexaenoic Acid-Enhanced Autophagic Flux Improves Cardiac Dysfunction after Myocardial Infarction by Targeting the AMPK/mTOR Signaling Pathway.

Background and Purpose. Docosahexaenoic acid (DHA) is a type of polyunsaturated fatty acid enriched in cod liver oil and seaweed. It is necessary for the human body and has important functions, such as antioxidation and antiatherosclerosis activities. Long-term oral administration of DHA or the use of DHA at the initial stage of ischemia can increase the level of autophagy and exert a protective effect on neurological functions related to cerebral infarction. However, the effect of DHA on myocardial injury and cardiac insufficiency after myocardial infarction (MI) is unknown. This study was aimed at exploring whether DHA plays a protective role in AMI and its specific molecular mechanism. Experimental Method. In vitro cardiomyocyte hypoxia and in vivo MI injury models were used to determine the role of DHA in MI. Hypoxic injury induced damage in cultured neonatal mouse cardiomyocytes (NMCs). The C57BL/6J mouse MI model was established by permanent ligation of the left anterior descending branch. Main Results. DHA improved the cardiomyocyte viability of NMCs induced by hypoxia injury and reduced cell necrosis. DHA reduced infarct size, improved heart function, and reduced the degree of myocardial fibrosis in mice after MI. In addition, DHA enhanced autophagy flux and reduced apoptosis in vitro and in vivo. In addition, we found that chloroquine, an autophagy inhibitor, blocked the protective effect of DHA on cardiomyocyte apoptosis and cardiac dysfunction, indicating that DHA exerts cardioprotective effects in part by promoting autophagy flux. We also observed that DHA enhanced autophagy flux by activating the AMPK/mTOR signaling pathway. Conclusions and Significance. In conclusion, our findings indicate for the first time that DHA improves MI-induced cardiac dysfunction by promoting AMPK/mTOR-mediated autophagic flux.

Post-interventional Evaluation and Follow-Up in Children With Patent Ductus Arteriosus Complicated With Moderate to Severe Pulmonary Arterial Hypertension: A Retrospective Study.

Background: Transcatheter closure is an important treatment for patent ductus arteriosus (PDA) complicated with moderate and severe pulmonary arterial hypertension (PAH). This report presents our experience with transcatheter closure of PDA complicated with moderate and severe PAH. Methods: The 49 cases of PDA complicated with moderate and severe PAH were collected in the Second Affiliated Hospital and Yuying Children's Hospital from January 2014 to December 2019 with transcatheter closure of PDA and follow-up. All patients were invited for transthoracic echocardiography, electrocardiogram, and thoracic radiography check-up. Results: Device implantation was successful in 48 of 49 patients (98.0%). Among them, 30 cases were in the PAH after defect correction (CD) group, and 19 examples were in the Non-PAH after defect correction (NCD) group. Pulmonary systolic pressure, left atrial diameter, and left ventricular end-diastolic diameter immediately after interventional therapy and 6 months later were lower than the pre-operative levels (p < 0.05). The incidence of the immediate residual shunt (RS) in this study was 34.9%, most of which were minimal amount shunt. RS disappeared in all patients within 1 year of therapy. Four patients had thrombocytopenia and one patient had left pulmonary artery stenosis. No other serious adverse event occurred during the follow-up period. The pressure gradient tricuspid valve regurgitation (PGTI) and the right heart catheterization (RHC) consistency points were 93.75% (15/16) and were within the 95% consistency limit by the Bland-Altman method. The Logistic regression analysis concluded that the pre-operative Pp/Ps and the narrowest diameter of PDA are risk factors for post-operative PAH (p < 0.05). The cut-off point of the pre-operative Pp/Ps and the narrowest diameter of PDA were calculated to be 0.595 and 4.75 mm, respectively. Conclusion: Interventional occlusion in children with PDA complicated with moderate and severe PAH is safe, effective, and has few complications. Targeted drug therapy has a good clinical effect. The narrowest diameter of PDA and the pre-operative Pp/Ps may be one of the risk factors of residual PAH after interventional therapy.

STAT3 Suppresses Cardiomyocytes Apoptosis in CVB3-Induced Myocarditis Via Survivin.

Background: Viral myocarditis (VMC) is a common inflammatory cardiovascular disease with unclear mechanisms, which mainly affects children and adolescents. Apoptosis is the key to CVB3-induced myocarditis, and blocking this process may be beneficial to the therapy of VMC. Hence, this study aimed to explore the protective function of STAT3 on cardiomyocyte apoptosis of VMC and its underlying mechanisms. Methods and Results: In this research, we confirmed that STAT3 was significantly activated in both animal and cell models of VMC. To further clarify what role did STAT3 play in VMC, AG490, an inhibitor of STAT3, was used to suppress p-STAT3. Our results demonstrated that decreased expression of p-STAT3 caused by AG490 significantly aggravated severity of VMC with elevated myocardial inflammation, deteriorative ventricular systolic function and increased mortality. It suggested that STAT3 plays a protective role in VMC. To further identify the anti-apoptosis impact that activated STAT3 made, we constructed lentivirus to regulate the expression of STAT3 in NMCs. We found that up-regulated activated STAT3 attenuated cardiomyocyte apoptosis, but down-regulated one aggravated that, which verified activated STAT3 played an anti-apoptosis role in VMC. Following that, we explored what elements are involved in the anti-apoptotic mechanism of activated STAT3 by using survivin inhibitor YM155. The result showed the anti-apoptotic effect of activated STAT3 does not work in the case of survivin inhibition. Conclusion: Our findings demonstrated STAT3 by targeting survivin alleviated cardiomyocyte apoptosis in CVB3-induced myocarditis.