Protección miocárdica

Basic Res Cardiol. 2025 Jun 15. doi: 10.1007/s00395-025-01122-z. Online ahead of print.

ABSTRACT

Ferroptosis is an important cause of cardiomyocyte loss and cardiac dysfunction. Cathelicidin-related antimicrobial peptide (CRAMP) is an endogenous polypeptide that regulates oxidative stress in the body and is involved in ferroptosis. However, its specific role and mechanism in ferroptosis are unclear. To analyze the role of CRAMP in ferroptosis, we first analyzed its expression in infarcted myocardial tissues, and verified its role in ferroptosis in vitro through overexpression and knock-down techniques. The activity and expression of cathepsin L (CTSL) and its effect on ferroptosis were analyzed to verify whether CTSL participated in ferroptosis as a downstream of CRAMP. Protein disulfide isomerase family A member 4 (PDIA4) was screened as an interacting protein of CTSL by using the database, and the role of PDIA4 in ferroptosis was analyzed by gene knockdown and overexpression. Finally, the regulatory mechanism of CRAMP in ferroptosis was verified in vivo by mouse myocardial infarction model. CRAMP levels were reduced in both infarcted cardiac tissues and cardiomyocytes exposed to ferroptosis inducers. The overexpression of CRAMP or pretreatment of LL-37 alleviated cardiomyocyte ferroptosis, whereas CRAMP knockdown exacerbated cell death. Under ferroptotic stress, the expression of CTSL was elevated. CRAMP inhibited ferroptosis by antagonizing the CTSL activity. Abnormal increase in CTSL activity and levels caused PDIA4 to decrease. Overexpression of PDIA4 inhibited ferroptosis induced by CTSL, while knocking down PDIA4 counteracted the protection of CRAMP. In vivo, both CRAMP overexpression and administration of CRAMP peptide significantly ameliorated myocardial injury and improved cardiac function. CRAMP increases PDIA4 levels by inhibiting the activity of CTSL and antagonizes ferroptosis in cardiomyocytes. Targeting CRAMP offers innovative therapeutic strategies and insights for the prevention and management of myocardial injury.

PMID:40517353 | DOI:10.1007/s00395-025-01122-z

Acta Biomater. 2025 Jun 12:S1742-7061(25)00433-7. doi: 10.1016/j.actbio.2025.06.018. Online ahead of print.

ABSTRACT

Copper overload induces a unique form of cell death called cuproptosis via mitochondrial ROS accumulation. Following myocardial infarction (MI), copper ion levels rise significantly in infarcted tissue. Cardiomyocytes, highly sensitive to copper, respond through activation and nuclear translocation of LRP6, which interacts with ALKBH5 to suppress m6A modification of ferredoxin 1 (FDX1), thereby exacerbating copper toxicity. LRP6 also facilitates copper influx, further promoting cuproptosis. High-throughput screening identified chrysin-7-O-glucuronide (C7Og) as a potent LRP6 inhibitor that mitigates cuproptosis without compromising cardiac protective effects. Moreover, a Janus hydrogel enhanced with benzalkonium chloride-modified tannic acid improves tissue adhesion and glucose delivery. A myocardial patch integrating C7Og within this hydrogel significantly reduced infarct size and improved cardiac function in both rat and Bama miniature pig models, highlighting strong translational potential for MI therapy. STATEMENT OF SIGNIFICANCE: This study uncovers a mechanism of copper-induced cell death, termed cuproptosis, in myocardial infarction (MI). It identifies low-density lipoprotein receptor-related protein 6 (LRP6) as a key regulator of copper influx and cuproptosis, revealing a potential target for mitigating copper toxicity in cardiac tissue. Chrysin-7-O-glucuronide (C7Og), a potent LRP6 inhibitor, offers a promising strategy to prevent LRP6-mediated cell death while preserving its protective role in cardiac function. Encapsulating C7Og in a Janus hydrogel enhances its delivery and adhesion, demonstrating significant efficacy in reducing myocardial damage and improving cardiac function in rat and Bama miniature pig models. This work offers new insights into copper homeostasis and presents a potential therapeutic approach for MI treatment.

PMID:40516843 | DOI:10.1016/j.actbio.2025.06.018

Chin Med. 2025 Jun 13;20(1):86. doi: 10.1186/s13020-025-01128-8.

ABSTRACT

BACKGROUND: The heart, as the body's blood-pumping organ, is extremely sensitive to changes in oxygen levels. Myocardial injury caused by hypoxia is a challenging issue, and there are currently no definitive specific drugs available for its treatment. Ginsenoside Rg5, one of the main rare saponins in ginseng, has shown significant efficacy in treating myocardial injury. This study aims to investigate the role and mechanisms of Rg5 in the treatment of hypoxic myocardial injury.

METHODS: The cardioprotective effect against acute hypoxia of Rg5 was studied by assessing heart function, myocardial injury markers, inflammation, and oxidative stress in C57 mice, as well as apoptosis and reactive oxygen species (ROS) levels in H9c2 cardiomyocytes. Thermal proteome and target validation techniques were used to confirm the target protein of Rg5. The further protective mechanisms against hypoxia-induced damage were explored using immunocoprecipitation, immunofluorescence and rescue experiments in vivo and in vitro.

RESULTS: The experimental results demonstrated that Rg5 effectively improved cardiac function in mice, reduced inflammation, oxidative stress, and the release of myocardial injury markers, decreased cardiomyocyte apoptosis, and lowered ROS levels. Further, using target protein screening and validation techniques, Signal transducer and activator of transcription 3 (STAT3) was verified as a direct target for Rg5's cardioprotective effect. It was observed that Rg5 specifically promoted the phosphorylation of Tyr705 in STAT3 via the JAK2/STAT3 pathway, leading to the translocation of phosphorylated STAT3 into the nucleus where they induce the expression of anti-apoptotic protein and protect cells from hypoxic damage.

CONCLUSION: Rg5 could be a potential therapeutic agent for preventing and treating myocardial hypoxic injury, providing scientific evidence for its application in anti-hypoxic therapy.

PMID:40514732 | PMC:PMC12166643 | DOI:10.1186/s13020-025-01128-8

J Nanobiotechnology. 2025 Jun 13;23(1):439. doi: 10.1186/s12951-025-03474-z.

ABSTRACT

BACKGROUND: Acute myocardial infarction remains a leading cause of mortality, with ischemia-reperfusion (I/R) injury causing severe myocardial damage through mitochondrial dysfunction. While mesenchymal stem cell-derived exosomes (MSC-Exo) show therapeutic potential, their limited targeting and insufficient mitochondrial protection restrict clinical application.

RESULTS: We developed a novel engineered exosome platform (Exo-I-S) using an IRES-driven bicistronic plasmid to co-load Sirtuin3 (SIRT3) and GPI-Insulin, aiming to enhance targeting efficiency and mitochondrial protection. The platform was evaluated in both in vitro and in vivo models of myocardial I/R injury. In vitro, Exo-I-S achieved faster cellular uptake, improved mitochondrial function, and reduced oxidative stress in H9c2 cells. The platform activated PI3K/AKT signaling, enhanced Glut4 translocation, and improved mitochondrial respiratory capacity. In a rat I/R injury model, Exo-I-S significantly reduced infarction size, improved cardiac function, and enhanced glucose metabolism, with superior therapeutic outcomes compared to unmodified exosomes.

CONCLUSIONS: The dual functionality of Exo-I-S, combining insulin-mediated targeting with SIRT3-driven mitochondrial protection, provides a promising strategy for I/R injury treatment. Future studies should focus on optimizing targeting specificity and developing sustained release mechanisms to enhance clinical applicability.

PMID:40514650 | PMC:PMC12164078 | DOI:10.1186/s12951-025-03474-z

Nat Cardiovasc Res. 2025 Jun;4(6):761-772. doi: 10.1038/s44161-025-00657-7. Epub 2025 Jun 13.

ABSTRACT

Data on the cardiovascular-kidney effects and safety of empagliflozin among patients with acute myocardial infarction are limited. EMPACT-MI (Study to Evaluate the Effect of Empagliflozin on Hospitalization for Heart Failure and Mortality in Patients with Acute Myocardial Infarction) was a double-blind, multicenter clinical trial that randomized 6,522 patients with acute myocardial infarction and risk for heart failure to empagliflozin or placebo. Here we show in this secondary analysis that the mean estimated glomerular filtration rate at baseline was 76.1 ml min-1 1.73 m-2 (s.d. = 19.9 ml min-1 1.73 m-2), with longitudinal kidney function data available for 1,152 (17.7%) treated patients from select countries. By 24 months, compared with baseline, the estimated glomerular filtration rate was similar in the empagliflozin group but declined in the placebo group (P = 0.01). Empagliflozin reduced the total adverse events of heart failure or all-cause mortality irrespective of kidney function (Pinteraction = 0.30). Thirty-day adverse event rates were similar by treatment group and consistent across baseline kidney function. Empagliflozin had kidney-protective effects, reduced heart failure outcomes and was safe to initiate soon after acute myocardial infarction across baseline kidney function.

PMID:40514435 | PMC:PMC12170341 | DOI:10.1038/s44161-025-00657-7

Cell Transplant. 2025 Jan-Dec;34:9636897251347389. doi: 10.1177/09636897251347389. Epub 2025 Jun 13.

ABSTRACT

Myocardial ischemia-reperfusion injury (MIRI), which occurs when the blood supply is restored in the ischemic myocardium, is a major medical concern for patients with acute myocardial infarction (AMI). Despite the use of extracellular vesicles (EVs) from mesenchymal stromal cells (MSCs), which can be used to treat MIRI, the application of EVs still has limited use in clinical practice. Melatonin (MT), however, not only exerts a significant protective effect in the treatment of cardiovascular diseases but also enhances biological functions of MSCs through pretreatment. Therefore, in the current study, we sought to determine whether MT improves the paracrine effect of MSCs through pretreatment. Our research provides evidence to support the therapeutic effect of MT-pretreated MSCs-derived extracellular vesicles (MT-EVs) in ameliorating hypoxia/reoxygenation (H/R) injury in human umbilical vein endothelial cells (HuVECs). We also performed a metabolomic analysis using ultra-high-performance liquid chromatography/Q Exactive HF-X Hybrid Quadrupole-Orbitrap Mass (UHPLC-QE-MS/MS) to explore metabolism profiling of H/R cell model with MT-EVs or EVs from MSCs (NC-EVs) treatment. We found 932 differential metabolites (DEMs) in the MT-EVs group compared with the NC-EVs group. Metabolic profiling analysis showed these metabolites were engaged in the ABC transporters, nucleotide metabolism, purine metabolic pathway, and glycerophospholipid metabolism. Furthermore, we observed increased levels of palmitoylcarnitine (fatty acid-derived mitochondrial substrate) and gabapentin in the MT-EVs group, which may play a therapeutic role in HuVECs during H/R. In conclusion, the results demonstrated that MT-EVs can protect endothelial cells from H/R injury by affecting the metabolic pathways.

PMID:40514195 | PMC:PMC12171273 | DOI:10.1177/09636897251347389

Metabolism. 2025 Jun 11;170:156326. doi: 10.1016/j.metabol.2025.156326. Online ahead of print.

ABSTRACT

Ubiquitin-specific protease 48 (USP48) plays an important role in the regulation of DNA repair and immune signaling in health and diseases. Nonetheless, its implication in the development of diabetes-accelerated myocardial ischemia/reperfusion (I/R) injury (MI/RI) has yet to be clarified. Diabetic mice were constructed by streptozotocin (STZ) injection, and MI/RI was then induced by coronary artery occlusion and reperfusion. H9c2 cells were exposed to high glucose (HG) for 24 h, followed by hypoxia/reoxygenation (H/R) for 4 and 2 h, respectively. USP48 protein and mRNA levels were downregulated in MI/RI mice or H/R-exposed cardiomyocytes, but were unexpectedly upregulated in diabetic mice following MI/RI and H9c2 cells exposed to HG and H/R. Cardiac-specific deficiency of USP48 worsened cardiac dysfunction, increased post-ischemic infarction size, promoted mitochondrial damage in myocardial cells, accelerated cardiomyocyte inflammation, oxidative stress, and apoptosis in diabetic mice. Conversely, such pathological conditions were ameliorated by cardiac-specific overexpression of USP48. Proteomics and experimental validation showed that USP48 stabilized and upregulated calponin 1 (CNN1) to confer cardioprotection, since silencing CNN1 minimized the benefits of USP48 in diabetes-aggravated cardiomyocyte injury. RNA sequencing and experimental data demonstrated that the USP48/CNN1 axis inhibited the release of CXC motif chemokine ligand 1 (CXCL1) and CXCL2 through inactivating the ERK1/2 pathway. Eventually, blockade of CXCL1/2 with specific antibodies protected against diabetes-exacerbated MI/RI, akin to USP48 overexpression. Together, these results highlight USP48 as a potential therapeutic target for managing diabetes-aggravated MI/RI by regulating the CNN1/ERK1/2/CXCL1/2 signaling pathway.

PMID:40513941 | DOI:10.1016/j.metabol.2025.156326

Biochim Biophys Acta Mol Cell Res. 2025 Jun 11;1872(7):120006. doi: 10.1016/j.bbamcr.2025.120006. Online ahead of print.

ABSTRACT

OBJECTIVE: The present study aimed to investigate the role of delphinidin (Dp) in myocardial ischemia-reperfusion injury (MIRI) and elucidate the underlying mechanism.

METHODS: MIRI animal models were established in Sprague-Dawley rats by ligation of left anterior descending coronary artery (LAD) ligation for 30 min and reperfusion of 2 h. Primary cardiomyocytes and H9C2 cells were stimulated by oxygen-glucose deprivation/regain (OGD/R) conditions for mimicking MIRI cell models. Ultrasound, hematoxylin and eosin and Masson staining were used to evaluate cardiac function and myocardial infarction in rats following Dp treatment. Cell counting kit-8 assay and flow cytometry were performed to detect cell viability and apoptosis, respectively. Western blotting and quantitative real-time polymerase chain reaction measured ALOX15 expression. Additionally, ferroptosis-related factors and lactate dehydrogenase levels were detected using commercial kits.

RESULTS: In MIRI rats, Dp treatment dose-dependently increased the left ventricular ejection fraction (EF) and fractional shortening (FS) while reduced the left ventricular internal diameter in diastole (LVIDd) and systole (LVIDs). The increase of necrosis and fibrosis in cardiac tissues of MIRI rats were relieved by Dp. Dp treatment inhibited the apoptosis and ferroptosis of cardiomyocytes both in vivo and in vitro. Mechanically, Dp docked with a ferroptosis-related protein ALOX15 to induce its degradation. Moreover, ferroptosis activator erastin and ALOX15 overexpression reversed the protective effects of Dp on cardiomyocytes.

CONCLUSION: Dp inhibited ferroptosis by molecular docking ALOX15 and inducing its degradation, thereby improving MIRI.

PMID:40513616 | DOI:10.1016/j.bbamcr.2025.120006

Chin J Integr Med. 2025 Jun 13. doi: 10.1007/s11655-025-4017-4. Online ahead of print.

ABSTRACT

OBJECTIVE: To investigate cisplatin-induced cardiovascular toxicity and explore the protective effects and potential mechanism of curcumin co-treatment.

METHODS: Forty adult male Sprague-Dawley rats were numbered and randomly divided into control group, cisplatin group (7.5 mg/kg, once a week, for 2 weeks), curcumin group (200 mg/kg per day, for 2 weeks) and cisplatin+curcumin group (cisplatin 7.5 mg/kg, once a week, and curcumin 200 mg/kg per day for 2 weeks) by a random number table method, with 10 rats in each group. Cardiac and vascular morphology and functions were assessed using hematoxylin-eosin and Masson's trichrome staining, serum indexes detection, echocardiography, electrocardiogram (ECG), blood pressure monitoring, vascular ring isometric tension measurement, and left ventricular pressure evaluation. The expressions of extracellular signal-regulated kinases (ERK) and phosphorylated-ERK (p-ERK) were analyzed by immunohistochemical staining.

RESULTS: Cisplatin treatment induced notable cardiac alteration, as evidenced by changes in cardiac morphology, elevated serum enzymes (P<0.05), ECG abnormalities, and increased left ventricular end-diastolic pressure (P<0.05). Meanwhile, cisplatin significantly increased arterial pulse pressure (P<0.01), primarily due to a decrease in diastolic blood pressure. Severe fibrosis was also observed in the thoracic aorta wall. In vascular ring experiments, cisplatin treatment led to a significant reduction in phenylephrine-induced contraction (P<0.05) and acetylcholine-induced relaxation (P<0.01). Notably, Curcumin co-administration significantly alleviated cisplatin-induced cardiovascular damages, as demonstrated by improvement in these parameters. Furthermore, ERK expression in the myocardium and p-ERK expression in vascular smooth muscle cells were significantly upregulated following curcumin co-treatment.

CONCLUSIONS: Curcumin protects the heart and vasculature from cisplatin-induced damages, likely by upregulating ERK/p-ERK expression. These findings suggest that curcumin may serve as a promising therapeutic strategy for mitigating cisplatin-associated cardiovascular toxicity during tumor chemotherapy. In vitro cell culture experiments are needed to clarify the underlying mechanism.

PMID:40512365 | DOI:10.1007/s11655-025-4017-4

Cell Mol Life Sci. 2025 Jun 13;82(1):232. doi: 10.1007/s00018-025-05741-6.

ABSTRACT

OBJECTIVE: In this study, we sought to determine the significant impact of the vascular endothelial endoplasmic reticulum (ER) stress C/EBP homologous protein (CHOP) in renovascular hypertension-induced vascular endothelial dysfunction and cardiac fibrosis.

APPROACH AND RESULTS: Eight-week-old male and female CHOPflox/flox and ECCHOP-/- mice were randomly divided into eight groups with and without 2-Kidney-1-Clip (2K1C) surgery for four weeks. Body weight, systolic blood pressure, running performance, cardiac hypertrophy and fibrosis, lung edema, inflammation, vascular endothelial function, and signaling were assessed. For the mechanism, we utilized human coronary endothelial cells, both with and without CHOP down-regulation, and then stimulated them with and without angiotensin II ± ATP to determine eNOS phosphorylation level and the presence of inflammatory factors. Male and female CHOPflox/flox mice subjected to 2K1C for four weeks exhibited hypertension, cardiac hypertrophy and fibrosis, lung edema, impaired running performance, endothelium-dependent vascular relaxation dysfunction, reduction in eNOS phosphorylation, and inflammation induction. In contrast, male and female ECCHOP-/- mice subjected to 2K1C for four weeks were protected against the pathogenesis of renovascular hypertension. In vitro, data showed that deletion of CHOP in endothelial cells protected eNOS phosphorylation level and blunted the induction of inflammation in response to angiotensin II ± ATP.

CONCLUSION: Our research findings determined that CHOP is a central mechanism driving vascular endothelial dysfunction and cardiac fibrosis in renovascular hypertension. Therefore, targeting CHOP in endothelial cells could be a potential therapeutic approach to protect against the pathogenesis of renovascular hypertension.

PMID:40512182 | PMC:PMC12165939 | DOI:10.1007/s00018-025-05741-6

Molecules. 2025 May 31;30(11):2425. doi: 10.3390/molecules30112425.

ABSTRACT

The genus Clinopodium L. (Lamiaceae) comprises perennial herbaceous plants known for their diverse pharmacological properties. Clinically, these plants are mainly used for the treatment of various hemorrhagic disorders. This review systematically summarizes the research progress on the chemical composition, pharmacological activity, quality control, toxicity, and pharmacokinetics of the genus Clinopodium by searching Google Scholar, Scopus-Elsevier, Wiley, Springer, Taylor & Francis, Medline, Web of Science, CNKI, Weipu, Wanfang, and other academic databases over the last decade (March 2015-February 2025). To date, more than one hundred and thirty structurally diverse secondary metabolites have been isolated and identified from this genus, including flavonoids, triterpenoid saponins, diterpenoid glycosides, lignans, and phenylpropanoids. In addition, numerous volatile oil constituents have been identified in over forty species of the genus Clinopodium. Crude extracts and purified compounds exhibit a variety of pharmacological activities, including hemostatic, anti-myocardial cell injury, cardiovascular protective, anti-inflammatory, antimicrobial, antitumor, hypoglycemic, and insecticidal properties. However, current quality assessment protocols in the genus Clinopodium are limited to flavonoid- and saponin-based evaluations in C. chinense (Benth.) O. Kuntze and C. gracile (Benth.) O. Matsum. Further research is needed to elucidate the pharmacological mechanisms, toxicity, and possible interactions with other drugs. Therefore, the genus Clinopodium has a wide range of biologically active compounds with potential applications in drug development for hemostasis and cardiovascular protection. Nevertheless, there is also an urgent need to establish standardized methodologies to address uncertainties concerning the safety and efficacy of injectable extracts or compounds.

PMID:40509312 | PMC:PMC12156807 | DOI:10.3390/molecules30112425

J Clin Med. 2025 Jun 3;14(11):3947. doi: 10.3390/jcm14113947.

ABSTRACT

Background/Objectives: The complement system (particularly C5b-9) is an instrumental part of the induction and progression of atherosclerosis. The fluid phase C5b-9, also known as soluble C5b-9 (sC5b-9), is a reliable indicator of terminal complement pathway activation. Response Gene to Complement (RGC)-32 is a C5b-9 effector involved in cell cycle regulation and differentiation, immunity, tumorigenesis, obesity, and vascular lesion formation. RGC-32 regulates the expression of Sirtuin1 (SIRT1), known to delay vascular aging. The aim of this study was to assess the levels of sC5b-9, RGC-32, and SIRT1 in patients with atherosclerotic chronic and acute ischemic coronary syndromes. Methods: We determined the levels of sC5b-9, serum RGC-32, and SIRT1 by enzyme-linked immunosorbent assays (ELISAs) in 41 patients with chronic atherosclerotic coronary syndromes, 36 patients with acute ischemic coronary syndromes, and 21 asymptomatic controls with no history of ischemic heart disease. Results: sC5b-9 was significantly higher in patients with acute coronary syndrome as compared to the control group (p = 0.020, AUC = 0.702). In chronic coronary ischemia patients, serum RGC-32 was correlated with the extension of coronagraphically visualized atherosclerotic lesions (r = 0.352, p = 0.035) as well as with sC5b-9 levels (r = 0.350, p = 0.025). RGC-32 concentration was significantly lower in patients with acute coronary syndrome than in the control group (p = 0.020). We also observed significantly lower serum SIRT1 concentrations in patients with chronic ischemic heart disease than in the control group (p = 0.025). Conclusions: sC5b-9 may function as a possible biomarker for myocardial tissue damage in acute coronary syndrome. In acute coronary syndrome settings, low levels of RGC-32 may indicate a protective, antifibrotic function of RGC-32 in the ischemia-damaged myocardium; however, in stable chronic disease, RGC-32 serum values appear to correlate with the extent of atherosclerotic lesions, suggesting a pro-atherogenic role for RGC-32. Chronic myocardial ischemia decreases SIRT1 protein levels in serum, which underscores the use of SIRT1-modulating drugs in these patients.

PMID:40507709 | PMC:PMC12156031 | DOI:10.3390/jcm14113947