Bestrophin3 Deficiency in Vascular Smooth Muscle Cells Activates MEKK2/3–MAPK Signaling to Trigger Spontaneous Aortic Dissection

Circulation, Journal Year: 2023, Volume and Issue: 148(7), P. 589 - 606

Published: May 19, 2023

BACKGROUND: Aortic dissection (AD) is a fatal cardiovascular disorder without effective medications due to unclear pathogenic mechanisms. Bestrophin3 (Best3), the predominant isoform of bestrophin family in vessels, has emerged as critical for vascular pathological processes. However, contribution Best3 diseases remains elusive. METHODS: Smooth muscle cell–specific and endothelial knockout mice (Best3 SMKO ECKO , respectively) were engineered investigate role pathophysiology. Functional studies, single-cell RNA sequencing, proteomics analysis, coimmunoprecipitation coupled with mass spectrometry performed evaluate function vessels. RESULTS: expression aortas human AD samples mouse models was decreased. but not spontaneously developed age, incidence reached 48% at 72 weeks age. Reanalysis transcriptome data revealed that reduction fibromyocytes, fibroblast-like smooth cell cluster, typical feature ascending aneurysm. Consistently, deficiency cells decreased number fibromyocytes. Mechanistically, interacted both MEKK2 MEKK3, this interaction inhibited phosphorylation serine153 MEKK3 serine61. induced phosphorylation-dependent inhibition ubiquitination protein turnover MEKK2/3, thereby activating downstream mitogen-activated kinase signaling cascade. Furthermore, restoration or MEKK2/3 prevented progression angiotensin II–infused ApoE −/− mice. CONCLUSIONS: These findings unveil regulating phenotypic switch aortic structural integrity through controlling degradation. Best3–MEKK2/3 represents novel therapeutic target AD.

Language: Английский

---

EDIL3/Del-1 prevents aortic dissection through enhancing internalization and degradation of apoptotic vascular smooth muscle cells

Autophagy, Journal Year: 2024, Volume and Issue: unknown, P. 1 - 21

Published: June 14, 2024

Thoracic aortic dissection (TAD) is a severe disease, characterized by numerous apoptotic vascular smooth muscle cells (VSMCs). EDIL3/Del-1 secreted protein involved in macrophage efferocytosis acute inflammation. Here, we aimed to investigate whether EDIL3 promoted the internalization and degradation of VSMCs during TAD. The levels were decreased serum tissue from TAD mice. Global

Language: Английский

---

Adventitial Fibroblasts in Aortic Aneurysm: Unraveling Pathogenic Contributions to Vascular Disease

Diagnostics, Journal Year: 2022, Volume and Issue: 12(4), P. 871 - 871

Published: March 31, 2022

Aortic aneurysm (AA) is a degenerative vascular disease that involves aortic dilatation, and, if untreated, it can lead to rupture. Despite its significant impact on the healthcare system, multifactorial nature and elusive pathophysiology contribute limited therapeutic interventions prevent progression of AA. Thus, further research into mechanisms underlying AA paramount. Adventitial fibroblasts are one key constituents wall, they play an essential role in maintaining vessel structure function. However, adventitial remain understudied when compared with endothelial cells smooth muscle cells. facilitate production extracellular matrix (ECM), providing structural integrity. during biomechanical stress and/or injury, be activated myofibroblasts, which move site injury secrete collagen cytokines, thereby enhancing inflammatory response. The overactivation or persistence myofibroblasts has been shown initiate pathological remodeling. Therefore, understanding involved activation regulating myofibroblast may provide potential target delay This review discusses mechanistic insights associated remodeling, thus illustrating contribution pathogenesis

Language: Английский

---

Research Progress on the Pathogenesis of Aortic Aneurysm and Dissection in Metabolism

Current Problems in Cardiology, Journal Year: 2023, Volume and Issue: 49(1), P. 102040 - 102040

Published: Aug. 17, 2023

Language: Английский

---

A Dual‐Targeting, Multi‐Faceted Biocompatible Nanodrug Optimizes the Microenvironment to Ameliorate Abdominal Aortic Aneurysm

Advanced Materials, Journal Year: 2024, Volume and Issue: 36(33)

Published: June 24, 2024

Abdominal aortic aneurysm (AAA) is a highly lethal cardiovascular disease that currently lacks effective pharmacological treatment given the complex pathophysiology of disease. Here, single-cell RNA-sequencing data from patients with AAA and mouse model are analyzed, which reveals pivotal pathological changes, including M1-like polarization macrophages loss contractile function in smooth muscle cells (SMCs). Both cell types express integrin αvβ3, allowing for their dual targeting single rationally designed molecule. To this end, biocompatible nanodrug, termed EVMS@R-HNC, consists multifunctional drug everolimus (EVMS) encapsulated by hepatitis B virus core protein modifies to contain RGD sequence specifically bind αvβ3 designed. vitro vivo results show EVMS@R-HNC can target as well SMCs. Upon binding EVMS released intracellularly where it exhibits multiple functions, inhibiting M1 macrophage polarization, thereby suppressing self-propagating inflammatory cascade immune microenvironment imbalance, while preserving normal Collectively, these suggest presents promising therapeutic approach management AAA.

Language: Английский

---

Cannabidiol protects against acute aortic dissection by inhibiting macrophage infiltration and PMAIP1-induced vascular smooth muscle cell apoptosis

Journal of Molecular and Cellular Cardiology, Journal Year: 2024, Volume and Issue: 189, P. 38 - 51

Published: Feb. 20, 2024

Acute aortic dissection (AAD) progresses rapidly and is associated with high mortality; therefore, there remains an urgent need for pharmacological agents that can protect against AAD. Herein, we examined the therapeutic effects of cannabidiol (CBD) in AAD by establishing a suitable mouse model. In addition, performed human single-cell RNA sequencing bulk to elucidate potential underlying mechanism CBD. Pathological assays vitro studies were verify results bioinformatic analysis explore function β-aminopropionitrile (BAPN)-induced model, CBD reduced AAD-associated morbidity mortality, alleviated abnormal enlargement ascending aorta arch, suppressed macrophage infiltration vascular smooth muscle cell (VSMC) apoptosis. Bioinformatic revealed pro-apoptotic gene PMAIP1 was highly expressed samples, could inhibit Pmaip1 expression mice. Using VSMCs (HAVSMCs) co-cultured M1 macrophages, HAVSMCs mitochondrial-dependent apoptosis suppressing BAPN-induced overexpression macrophages. potentially mediates regulating Bax Bcl2 expression. Accordingly, mortality mitigated progression The CBD-induced mediated (primarily macrophages)-induced VSMC Our findings offer novel insights into macrophages interaction during progression, highlighting as candidate treatment.

Language: Английский

---

miRNA Regulation of Cell Phenotype and Parietal Remodeling in Atherosclerotic and Non-Atherosclerotic Aortic Aneurysms: Differences and Similarities

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(5), P. 2641 - 2641

Published: Feb. 24, 2024

Aortic aneurysms are a serious health concern as their rupture leads to high morbidity and mortality. Abdominal aortic (AAAs) thoracic (TAAs) exhibit differences similarities in pathophysiological pathogenetic features. AAA is multifactorial disease, mainly associated with atherosclerosis, characterized by relevant inflammatory response calcification. TAA rarely atherosclerosis some cases genetic mutations such Marfan syndrome (MFS) bicuspid valve (BAV). MFS-related non-genetic or sporadic share degeneration endothelial-to-mesenchymal transition (End-Mt) fibrosis, whereas BAV TAA, calcification prevails. microRNA (miRNAs) contribute the regulation of aneurysmatic remodeling. miRNAs class non-coding RNAs, which post-transcriptionally regulate gene expression. In this review, we report involvement deregulated different remodeling characterizing AAAs TAAs. AAA, miRNA deregulation appears be involved parietal response, smooth muscle cell (SMC) apoptosis wall promotes End-Mt, SMC myofibroblastic phenotypic switching fibrosis glycosaminoglycan accumulation. sustains Those may support development more personalized therapeutic approaches.

Language: Английский

---

Influence of DNA Methylation on Vascular Smooth Muscle Cell Phenotypic Switching

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(6), P. 3136 - 3136

Published: March 8, 2024

Vascular smooth muscle cells (VSMCs) are crucial components of the arterial wall, controlling blood flow and pressure by contracting relaxing artery walls. VSMCs can switch from a contractile to synthetic state, leading increased proliferation migratory potential. Epigenetic pathways, including DNA methylation, play role in regulating VSMC differentiation phenotypic flexibility. methylation involves attaching methyl group 5’ carbon cytosine base, which regulates gene expression interacting with transcription factors. Understanding key factors influencing plasticity may help identify new target molecules for development innovative drugs treat various vascular diseases. This review focuses on pathways VSMCs, summarizing mechanisms involved remodeling, significantly enhance our understanding related provide promising therapeutic approaches complex multifactorial

Language: Английский

---

The mitochondrial protease ClpP is a druggable target that controls VSMC phenotype by a SIRT1-dependent mechanism

Redox Biology, Journal Year: 2024, Volume and Issue: 73, P. 103203 - 103203

Published: May 21, 2024

Vascular smooth muscle cells (VSMCs), known for their remarkable lifelong phenotypic plasticity, play a pivotal role in vascular pathologies through ability to transition between different phenotypes. Our group discovered that the deficiency of mitochondrial protein Poldip2 induces VSMC differentiation both vivo and vitro. Further comprehensive biochemical investigations revealed Poldip2's specific interaction with ATPase caseinolytic protease chaperone subunit X (CLPX), which is regulatory proteolytic (ClpP) forms part ClpXP complex - proteasome-like evolutionarily conserved from bacteria humans. This limits protease's activity, reduced levels lead activation. finding prompted hypothesis activity within mitochondria may regulate phenotype. Employing gain-of-function loss-of-function strategies, we demonstrated significantly influences Notably, genetic pharmacological activation inhibits plasticity fosters quiescent, differentiated, anti-inflammatory The ClpP using TIC10, currently phase III clinical trials cancer, successfully replicates this phenotype vitro markedly reduces aneurysm development mouse model elastase-induced aortic aneurysms. mechanistic exploration indicates regulates by modifying cellular NAD+/NADH ratio activating Sirtuin 1. findings reveal crucial proteostasis regulation propose as novel, actionable target manipulating

Language: Английский

---

Current Prognostic Biomarkers for Abdominal Aortic Aneurysm: A Comprehensive Scoping Review of the Literature

Biomolecules, Journal Year: 2024, Volume and Issue: 14(6), P. 661 - 661

Published: June 5, 2024

Abdominal aortic aneurysm (AAA) is a progressive dilatation of the aorta that can lead to rupture. The pathophysiology disease not well characterized but known be caused by general breakdown extracellular matrix within wall. In this comprehensive literature review, all current research on proteins have been investigated for their potential prognostic capabilities in patients with AAA was included. A total 45 were found biomarkers AAA, predicting incidence rupture, growth, endoleak, and post-surgical mortality. fell into following seven categories based primary function: (1) cardiovascular health, (2) hemostasis, (3) transport proteins, (4) inflammation immunity, (5) kidney function, (6) cellular structure, (7) hormones growth factors. This most up-to-date review markers functions. outlines wide pathophysiological processes are implicated progression.

Language: Английский

---