Deficiency of filamin A in smooth muscle cells protects against hypoxia‑mediated pulmonary hypertension in mice

Zheng, Yaguo; Ma, Hong; Yan, Yufeng; Ye, Peng; Yu, Wande; Lin, Song; Chen, Shao‐Liang

doi:10.3892/ijmm.2023.5225

Cited by 4 publications

(2 citation statements)

References 46 publications

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“…Unfortunately, desmin belonging to type III contractile filaments can be found in different muscle cell types ( Di Conza et al, 2023 ). Likewise, α-SMA is a cytoskeletal protein and presents in smooth-muscle cells and fibroblasts ( Zheng et al, 2023 ). RGS-5 is a protein that activates GTPase proteins and disrupts sphingosine-1-phosphate, endothelin-1, angiotensin II, and PDGF-induced signaling in cultured cells ( Bondjers et al, 2003 ; Cho et al, 2003 ).…”

Section: Pericytes Function and Activitymentioning

confidence: 99%

Role of autophagy in angiogenic potential of vascular pericytes

Milani,

Rezabakhsh,

Karimipour

et al. 2024

Front. Cell Dev. Biol.

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The vasculature system is composed of a multiplicity of juxtaposed cells to generate a functional biological barrier between the blood and tissues. On the luminal surface of blood vessels, endothelial cells (ECs) are in close contact with circulating cells while supporting basal lamina and pericytes wrap the abluminal surface. Thus, the reciprocal interaction of pericytes with ECs is a vital element in the physiological activity of the vascular system. Several reports have indicated that the occurrence of pericyte dysfunction under ischemic and degenerative conditions results in varied micro and macro-vascular complications. Emerging evidence points to the fact that autophagy, a conserved self-digestive cell machinery, can regulate the activity of several cells like pericytes in response to various stresses and pathological conditions. Here, we aim to highlight the role of autophagic response in pericyte activity and angiogenesis potential following different pathological conditions.

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Section: Pericytes Function and Activitymentioning

confidence: 99%

Role of autophagy in angiogenic potential of vascular pericytes

Milani,

Rezabakhsh,

Karimipour

et al. 2024

Front. Cell Dev. Biol.

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“…As a highly prevalent cardiopulmonary disorder, pulmonary arterial hypertension (PAH) is characterized with diffused vascular remodeling and pulmonary artery resistance, resulting in subsequent right ventricular dysfunction [ 1 , 2 ]. Dysfunctional pulmonary arterial smooth muscle cells were manifested with abnormal proliferation and migration of PASMCs, together driving progressive remodeling of peripheral pulmonary arteries and augmented right ventricular afterload [ 3 , 4 ]. However, the cellular and molecular mechanism modulating hypoxic PAH remains undefined.…”

Section: Introductionmentioning

confidence: 99%

Elevated CHCHD4 orchestrates mitochondrial oxidative phosphorylation to disturb hypoxic pulmonary hypertension

Wang

Zeng

et al. 2023

J Transl Med

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Background Pulmonary arterial hypertension (PAH) is a highly prevalent cardiopulmonary disorder characterized by vascular remodeling and increased resistance in pulmonary artery. Mitochondrial coiled–coil–helix–coiled–coil–helix domain (CHCHD)-containing proteins have various important pathophysiological roles. However, the functional roles of CHCHD proteins in hypoxic PAH is still ambiguous. Here, we aimed to investigate the role of CHCHD4 in hypoxic PAH and provide new insight into the mechanism driving the development of PAH. Methods Serotype 1 adeno‐associated viral vector (AAV) carrying Chchd4 was intratracheally injected to overexpress CHCHD4 in Sprague Dawley (SD) rats. The Normoxia groups of animals were housed at 21% O2. Hypoxia groups were housed at 10% O2, for 8 h/day for 4 consecutive weeks. Hemodynamic and histological characteristics are investigated in PAH. Primary pulmonary artery smooth muscle cells of rats (PASMCs) are used to assess how CHCHD4 affects proliferation and migration. Results We found CHCHD4 was significantly downregulated among CHCHD proteins in hypoxic PASMCs and lung tissues from hypoxic PAH rats. AAV1-induced CHCHD4 elevation conspicuously alleviates vascular remodeling and pulmonary artery resistance, and orchestrates mitochondrial oxidative phosphorylation in PASMCs. Moreover, we found overexpression of CHCHD4 impeded proliferation and migration of PASMCs. Mechanistically, through lung tissues bulk RNA-sequencing (RNA-seq), we further identified CHCHD4 modulated mitochondrial dynamics by directly interacting with SAM50, a barrel protein on mitochondrial outer membrane surface. Furthermore, knockdown of SAM50 reversed the biological effects of CHCHD4 overexpression in isolated PASMCs. Conclusions Collectively, our data demonstrated that CHCHD4 elevation orchestrates mitochondrial oxidative phosphorylation and antagonizes aberrant PASMC cell growth and migration, thereby disturbing hypoxic PAH, which could serve as a promising therapeutic target for PAH treatment. Graphical Abstract

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Exosomes enriched by miR-429-3p derived from ITGB1 modified Telocytes alleviates hypoxia-induced pulmonary arterial hypertension through regulating Rac1 expression

Qi,

Zhang,

Yan

2024

Cell Biol Toxicol

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Background Recent studies have emphasized the critical role of Telocytes (TCs)-derived exosomes in organ tissue injury and repair. Our previous research showed a significant increase in ITGB1 within TCs. Pulmonary Arterial Hypertension (PAH) is marked by a loss of microvessel regeneration and progressive vascular remodeling. This study aims to investigate whether exosomes derived from ITGB1-modified TCs (ITGB1-Exo) could mitigate PAH. Methods We analyzed differentially expressed microRNAs (DEmiRs) in TCs using Affymetrix Genechip miRNA 4.0 arrays. Exosomes isolated from TC culture supernatants were verified through transmission electron microscopy and Nanoparticle Tracking Analysis. The impact of miR-429-3p-enriched exosomes (Exo-ITGB1) on hypoxia-induced pulmonary arterial smooth muscle cells (PASMCs) was evaluated using CCK-8, transwell assay, and inflammatory factor analysis. A four-week hypoxia-induced mouse model of PAH was constructed, and H&E staining, along with Immunofluorescence staining, were employed to assess PAH progression. Results Forty-five miRNAs exhibited significant differential expression in TCs following ITGB1 knockdown. Mus-miR-429-3p, significantly upregulated in ITGB1-overexpressing TCs and in ITGB1-modified TC-derived exosomes, was selected for further investigation. Exo-ITGB1 notably inhibited the migration, proliferation, and inflammation of PASMCs by targeting Rac1. Overexpressing Rac1 partly counteracted Exo-ITGB1’s effects. In vivo administration of Exo-ITGB1 effectively reduced pulmonary vascular remodeling and inflammation. Conclusions Our findings reveal that ITGB1-modified TC-derived exosomes exert anti-inflammatory effects and reverse vascular remodeling through the miR-429-3p/Rac1 axis. This provides potential therapeutic strategies for PAH treatment. Graphical Abstract 1. Identification of Differentially Expressed microRNAs (DEmiRs) in ITGB1 overexpressed TCs. 2. Effects of Exo-ITGB1 or miR-429-3p on Hypoxia-Induced PASMCs in vitro. 3. Exo-ITGB1 inhibits the hyper-proliferation and migration of PASMCs through regulating miR-429-3p/Rac1 axis in vitro. 4. The therapeutic potential of Exo-ITGB1 in hypoxia-induced PAH model in vivo.

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Deficiency of filamin A in smooth muscle cells protects against hypoxia‑mediated pulmonary hypertension in mice

Cited by 4 publications

References 46 publications

Role of autophagy in angiogenic potential of vascular pericytes

Role of autophagy in angiogenic potential of vascular pericytes

Elevated CHCHD4 orchestrates mitochondrial oxidative phosphorylation to disturb hypoxic pulmonary hypertension

Exosomes enriched by miR-429-3p derived from ITGB1 modified Telocytes alleviates hypoxia-induced pulmonary arterial hypertension through regulating Rac1 expression

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