Targeting endothelial tight junctions to predict and protect thoracic aortic aneurysm and dissection

European Heart Journal, Journal Year: 2023, Volume and Issue: 44(14), P. 1248 - 1261

Published: Jan. 14, 2023

Whether changes in endothelial tight junctions (TJs) lead to the formation of thoracic aortic aneurysm and dissection (TAAD) serve as an early indicator therapeutic target remains elusive.Single-cell RNA sequencing analysis showed aberrant TJ expressions aortas patients with TAAD. In a β-aminopropionitrile (BAPN)-induced TAAD mouse model, function was disrupted at stage (5 10 days) observed by vascular permeability assay, while intercellular distribution crucial components significantly decreased en face staining. For non-invasive detection function, two dextrans molecular weights 4 70 kDa were conjugated magnetic resonance imaging (MRI) contrast agent Gd-DOTA synthesize FITC-dextran-DOTA-Gd rhodamine B-dextran-DOTA-Gd. MRI images that both probes accumulated BAPN-fed mice. Particularly, mice increased signals from 5 days developed 14 days, whereas similar between time points did not. Furthermore, protease-activated receptor 2 inhibitor AT-1001, which seals TJs, alleviated BAPN-induced impairment expression subsequently reduced incidence. Notably, endothelial-targeted ZO-1 conditional knockout Mechanistically, inflammation edema mice, these phenomena attenuated AT-1001.The disruption is event prior formation, herein serving potential promising for

Language: Английский

---

Mitochondrial Dysfunction and Therapeutic Perspectives in Cardiovascular Diseases

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(24), P. 16053 - 16053

Published: Dec. 16, 2022

High mortality rates due to cardiovascular diseases (CVDs) have attracted worldwide attention. It has been reported that mitochondrial dysfunction is one of the most important mechanisms affecting pathogenesis CVDs. Mitochondrial DNA (mtDNA) mutations may result in impaired oxidative phosphorylation (OXPHOS), abnormal respiratory chains, and ATP production. In dysfunctional mitochondria, electron transport chain (ETC) uncoupled energy supply reduced, while reactive oxygen species (ROS) production increased. Here, we discussed analyzed relationship between mtDNA mutations, mitophagy, decreased OXPHOS, elevated ROS, CVDs from perspective dysfunction. Furthermore, explored current potential therapeutic strategies for by eliminating (e.g., editing replacement), enhancing improving OXPHOS capacity supplement with NAD+, nicotinamide riboside (NR), mononucleotide (NMN), nano-drug delivery), reducing ROS Coenzyme Q10 other antioxidants), dissected their respective advantages limitations. fact, some are still a long way achieving safe effective clinical treatment. Although establishing remains challenging, starting holds bright prospects.

Language: Английский

---

Reactive Oxygen Species and Oxidative Stress in Vascular-Related Diseases

Oxidative Medicine and Cellular Longevity, Journal Year: 2022, Volume and Issue: 2022, P. 1 - 11

Published: April 4, 2022

Oxidative stress (OS) refers to the enhancement of oxidation and decreased related antioxidant enzymes activity under pathological conditions, resulting in relatively excess reactive oxygen species (ROS), causing cytotoxicity, which leads tissue damage is linked neurodegenerative diseases, cardiovascular diabetes, cancers, many other pathologies. As an important intracellular signaling molecule, ROS can regulate numerous physiological actions, such as vascular reactivity neuronal function. According several studies, uncontrolled production injury. The growing evidence revealing how traditional risk factors translate into lead vasculitis diseases. In this review, we sought mainly discuss role mechanisms vascular-related especially common macrovascular

Language: Английский

---

Tetrahydrocurcumin improves lipopolysaccharide-induced myocardial dysfunction by inhibiting oxidative stress and inflammation via JNK/ERK signaling pathway regulation

Phytomedicine, Journal Year: 2022, Volume and Issue: 104, P. 154283 - 154283

Published: June 18, 2022

Acute myocardial dysfunction in patients with sepsis is attributed to oxidative stress, inflammation, and cardiomyocyte loss; however, specific drugs for its prevention are still lacking. Tetrahydrocurcumin (THC) has been proven contribute the of various cardiovascular diseases by decreasing stress inflammation. This study was performed investigate functions mechanism action THC septic cardiomyopathy.After oral administration (120 mg/kg) 5 consecutive days, a mouse model established via intraperitoneal lipopolysaccharide (LPS, 10 injection. Following this, cardiac function assessed, pathological section staining performed, inflammatory markers were detected.Myocardial systolic severely compromised parallel accumulation reactive oxygen species enhanced apoptosis mice sepsis. These adverse changes markedly reversed response treatment as well LPS-treated H9c2 cells. Mechanistically, inhibited release pro-inflammatory cytokines, including tumor necrosis factor alpha, interleukin (IL)-1β, IL-6, upregulating mitogen-activated protein kinase phosphatase 1, block phosphorylation c-Jun N-terminal (JNK) extracellular signal-regulated (ERK). Additionally, levels antioxidant proteins, nuclear factor-erythroid 2-related 2, superoxide dismutase NAD(P)H quinone oxidoreductase while gp91phox expression. Furthermore, upon treatment, Bcl-2 expression significantly increased, along decline Bax cleaved caspase-3 expression, which reduced loss.Our findings indicate that exhibited protective potential against cardiomyopathy reducing inflammation through regulation JNK/ERK signaling. The this provide basis further evaluation therapeutic agent cardiomyopathy.

Language: Английский

---

Melatonin alleviates cadmium-induced nonalcoholic fatty liver disease in ducks by alleviating autophagic flow arrest via PPAR-α and reducing oxidative stress

Poultry Science, Journal Year: 2023, Volume and Issue: 102(8), P. 102835 - 102835

Published: June 3, 2023

Cadmium (Cd) is an important environmental pollutant that causes liver damage and induces nonalcoholic fatty disease (NAFLD). NAFLD a fat accumulation has significant effects on the body. Melatonin (Mel) endogenous protective molecule with antioxidant, anti-inflammatory, antiobesity, antiaging effects. However, whether Mel can alleviate Cd-induced its mechanism remains unclear. First, in vivo, we found maintained mitochondrial structure function, inhibited oxidative stress, reduced injury. In addition, alleviated lipid induced by Cd. this process, inhibits acid production promotes oxidation. Interestingly, regulated PPAR-α expression autophagy blockade. vitro model, oil Red O staining, WB results showed accumulation. RAPA was used to activate accumulation, TG block flux aggravate After knocking down PPAR-α, autophagosome fusion lysosomes, autophagic increased alleviates attenuates restoring of flux.

Language: Английский

---

Melatonin rescues the mitochondrial function of bone marrow‐derived mesenchymal stem cells and improves the repair of osteoporotic bone defect in ovariectomized rats

Journal of Pineal Research, Journal Year: 2023, Volume and Issue: 76(1)

Published: Nov. 8, 2023

Abstract Osteoporotic bone defects, a severe complication of osteoporosis, are distinguished by delayed healing process and poor repair quality. While marrow‐derived mesenchymal stem cells (BMMSCs) the primary origin bone‐forming osteoblasts, their mitochondrial function is impaired, leading to inadequate regeneration in osteoporotic patients. Melatonin well‐known for its antioxidant properties regulation on metabolism. The present study postulated that melatonin has potential enhance defects restoring BMMSCs. In vitro administration at varying concentrations (0.01, 1, 100 μM) demonstrated significant dose‐dependent improvement BMMSCs obtained from ovariectomized rats (OVX‐BMMSCs), as indicated an elevation membrane potential, adenosine triphosphate synthesis expression respiratory chain factors. reduced level superoxide activating silent information regulator type 1 (SIRT1) downstream enzymes, particularly dismutase 2 (SOD2). protective effects were found be nullified upon silencing Sirt1 or Sod2 , underscoring crucial role SIRT1‐SOD2 axis melatonin‐induced enhancement energy metabolism OVX‐BMMSCs. To achieve sustained localized release melatonin, silk fibroin scaffolds loaded with (SF@MT) fabricated. involved surgical creation bilateral femur OVX rats, followed implantation SF@MT scaffolds. results application partially restored osteogenic differentiation OVX‐BMMSCs reinstating redox homeostasis. These findings suggest through implants holds therapeutic approach addressing defects.

Language: Английский

---

Animal Models, Pathogenesis, and Potential Treatment of Thoracic Aortic Aneurysm

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(2), P. 901 - 901

Published: Jan. 11, 2024

Thoracic aortic aneurysm (TAA) has a prevalence of 0.16–0.34% and an incidence 7.6 per 100,000 person-years, accounting for 1–2% all deaths in Western countries. Currently, no effective pharmacological therapies have been identified to slow TAA development prevent rupture. Large TAAs are treated with open surgical repair less invasive thoracic endovascular repair, both which high perioperative mortality risk. Therefore, there is urgent medical need identify the cellular molecular mechanisms underlying rupture develop new therapies. In this review, we summarize animal models including recent developments porcine zebrafish models: can assess therapeutic devices or intervention strategies large mammal employ large-scale small-molecule suppressor screening microwells. The second part review covers current views pathogenesis, derived from studies using these models, focus on roles transforming growth factor-beta (TGFβ) pathway vascular smooth muscle cell (VSMC)-elastin-contractile unit. last discusses treatment options as they emerge preclinical studies.

Language: Английский

---

Targeting the epigenome in in-stent restenosis: from mechanisms to therapy

Molecular Therapy — Nucleic Acids, Journal Year: 2021, Volume and Issue: 23, P. 1136 - 1160

Published: Jan. 26, 2021

Coronary artery disease (CAD) is one of the most common causes death worldwide. The introduction percutaneous revascularization has revolutionized therapy patients with CAD. Despite advent drug-eluting stents, restenosis remains main challenge in treating In-stent (ISR) indicates reduction lumen diameter after coronary intervention, which vessel's re-narrowing attributed to aberrant proliferation and migration vascular smooth muscle cells (VSMCs) dysregulation endothelial (ECs). Increasing evidence demonstrated that epigenetics involved occurrence progression ISR. In this review, we provide latest comprehensive analysis three separate but related epigenetic mechanisms regulating ISR, namely, DNA methylation, histone modification, non-coding RNAs. Initially, discuss mechanism restenosis. Furthermore, biological underlying diverse modifications modulating gene expression functions VSMCs, as well ECs Finally, potential therapeutic targets small molecule inhibitors cardiovascular factors. A more detailed understanding regulation essential for elucidating complex process, will assist developing improving ISR therapy.

Language: Английский

---

piRNA-823 is a novel potential therapeutic target in aortic dissection

Pharmacological Research, Journal Year: 2023, Volume and Issue: 196, P. 106932 - 106932

Published: Sept. 20, 2023

Aortic dissection (AD) presents a medical challenge for clinicians. Here, to determine the role of novel small non-coding piRNA-823 (piR-823) in AD, murine and human aorta from patients with AD were used. A high expression levels piR-823 found AD. Using performed loss- gain-of-function assays vitro vivo, we explore regulatory effect on vascular smooth muscle cells (VSMCs) obviously facilitates proliferation, migration, phenotypic transformation VSMCs or without nicotine treatment. directly binds suppresses histone deacetylase 1 (HDAC1) expression, regulates acetylation 3 (H3) via H3K9ac H3K27ac, eventually, VSMC functions To consolidate our findings, model was performed, observed that antagomir strongly inhibited pathogenesis through regulating remodeling. Thus, study finds potential target prevention treatment strategy nicotine-induced

Language: Английский

---

Dysregulation of interaction between LOX^high fibroblast and smooth muscle cells contributes to the pathogenesis of aortic dissection

Theranostics, Journal Year: 2021, Volume and Issue: 12(2), P. 910 - 928

Published: Dec. 15, 2021

Rationale: While cell-cell interaction plays a critical role in physiology and disease, comprehensive understanding of its dynamics vascular homeostasis diseases is yet absent. Methods: Here, by use single-cell RNA-sequencing multi-color staining, we delineate the cellular composition spatial characterization human aorta with or without aortic dissection (AD). Results: Scrutinization cell subtype alterations revealed significantly changed fibroblast (FB)-smooth muscle (SMC) interactions AD. Of these interactions, LOXhigh (fibroblast 2, FB2) diseased state exerted most pronounced effects on pathological deterioration SMCs In addition, pharmacologically targeting BMP (bone morphogenetic protein) signaling pathway effectively suppressed FB2 transition reduced AD incidence mice. Finally, COL5A1 (collagen type V alpha 1 chain), one secreted proteins released from FB2, was higher plasma patients than control patients, suggesting potential as biomarker for diagnosis. Conclusions: Our work not only identified pivotal specific FB progression, but also shed light diseases.

Language: Английский

---