Self-eating and Heart: The Emerging Roles of Autophagy in Calcific Aortic Valve Disease

Fan, Yunlong; Shao, Jiakang; Wei, Shixiong; Song, Chao; Li, Yanan; Jiang, Shengli

doi:10.14336/ad.2021.0101

Cited by 5 publications

(6 citation statements)

References 175 publications

(192 reference statements)

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“…In particular, cGMP-PKG is tightly correlated with diabetes vascular dysfunction and cardiomyocyte autophagy [ 39 – 41 ]. A reduction in autophagy leads to cardiac dysfunction, including cardiovascular calcification [ 42 , 43 ]. This evidence highlights the important relationship between the cGMP-PKG signalling pathway and VSMC autophagy.…”

Section: Discussionmentioning

confidence: 99%

Extracellular vesicle miR-32 derived from macrophage promotes arterial calcification in mice with type 2 diabetes via inhibiting VSMC autophagy

Cao

Chen

et al. 2022

J Transl Med

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Background The development of diabetes vascular calcification (VC) is tightly associated with the inhibition of vascular smooth muscle cell (VSMC) autophagy. Previously, our team found that miR-32-5p (miR-32) promotes macrophage activation, and miR-32 is expressed at higher level in the plasma of patients with coronary calcification. However, whether miR-32 mediates the function of macrophages in type 2 diabetes (T2D) VC is still unclear. Methods Wild-type (WT) and miR-32−/− mice were used in this study. qRT-PCR and western blotting were used to analyze gene expression. Flow cytometry was used to analyze the influence of glucose concentration on macrophage polarization. Nanoparticle tracking analysis (NTA), transmission electron microscopy, and confocal microscopy were used to identify macrophage extracellular vehicles (EVs). Immunofluorescence, in situ hybridization (ISH), immunohistochemistry, and alizarin red staining were used to analyze the influence of macrophage EVs on autophagy and calcification of the aorta of miR-32−/− mice. A luciferase assay was used to analyze the effect of miR-32 on myocyte enhancer factor 2D (Mef2d) expression. Co-IP combined with mass spectrometry (MS) and transcriptome sequencing was used to analyze the signalling pathway by which Mef2d acts in VSMC autophagy. Results We found that high glucose conditions upregulate miR-32 expression in macrophages and their EVs. Importantly, macrophages and their EVs promote VSMC osteogenic differentiation and upregulate miR-32 expression in VSMCs. Moreover, miR-32 mimics transfection promoted osteogenic differentiation and inhibited autophagy in VSMCs. In vitro and in vivo experiments showed that Mef2d is the key target gene of miR-32 that inhibits VSMC autophagy. Furthermore, MS and transcriptome sequencing found that cGMP-PKG is an important signalling pathway by which Mef2d regulates VSMC autophagy. In addition, after T2D miR-32−/− mice were injected with macrophage EVs via the caudal vein, miR-32 was detected in aortic VSMCs of miR-32−/− mice. Moreover, autophagy was significantly inhibited, and calcification was significantly enhanced in aorta cells. Conclusions These results reveal that EVs are the key pathway by which macrophages promote T2D VC, and that EVs miR-32 is a key cause of autophagy inhibition in VSMCs.

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Section: Discussionmentioning

confidence: 99%

Extracellular vesicle miR-32 derived from macrophage promotes arterial calcification in mice with type 2 diabetes via inhibiting VSMC autophagy

Cao

Chen

et al. 2022

J Transl Med

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“…There is a paucity of data on the role of autophagy biomarkers in the pathophysiology and progression of RHD and degenerative AS. AS has been reported to be associated with excessive deposition of misaligned collagen, glycoproteins, and osteogenic nodules [ 28 ]. The activation of autophagy reduces osteogenic activity, reduces calcification, and suppresses inflammation in calcific AS [ 28 ].…”

Section: Introductionmentioning

confidence: 99%

“…AS has been reported to be associated with excessive deposition of misaligned collagen, glycoproteins, and osteogenic nodules [ 28 ]. The activation of autophagy reduces osteogenic activity, reduces calcification, and suppresses inflammation in calcific AS [ 28 ]. Elevated autophagy biomarker levels are associated with increased cell death in heart failure [ 30 ].…”

Section: Introductionmentioning

confidence: 99%

“…Autophagy dysregulation has been reported in cancer, neurodegeneration, advanced age, and cardiovascular disease (CVD) [25][26][27]. Decreased autophagy is associated with aging and leads to giant cardiac mitochondria, reduced adenosine triphosphate (ATP) production and increased ROS levels [28]. The major molecular mediators of autophagy signalling include unc-51-like kinase 1 (ULK1), autophagy-related gene-phosphoinositide-interacting 1 (Atg-WIPI1), and vacuole protein sorting-Beclin 1 (Vps34-Beclin 1) class phosphoinositol-3-phosphate-kinase (PI3-kinase) complexes, autophagy-related gene 12 (Atg12), and protein 1 light chain 3 (LC3) conjugation systems [29].…”

Section: Introductionmentioning

confidence: 99%

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A study protocol to characterise pathophysiological and molecular markers of rheumatic heart disease and degenerative aortic stenosis using multiparametric cardiovascular imaging and multiomics techniques

Mutithu,

Aremu,

Mokaila

et al. 2024

PLoS ONE

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Introduction Rheumatic heart disease (RHD), degenerative aortic stenosis (AS), and congenital valve diseases are prevalent in sub-Saharan Africa. Many knowledge gaps remain in understanding disease mechanisms, stratifying phenotypes, and prognostication. Therefore, we aimed to characterise patients through clinical profiling, imaging, histology, and molecular biomarkers to improve our understanding of the pathophysiology, diagnosis, and prognosis of RHD and AS. Methods In this cross-sectional, case–controlled study, we plan to recruit RHD and AS patients and compare them to matched controls. Living participants will undergo clinical assessment, echocardiography, CMR and blood sampling for circulatory biomarker analyses. Tissue samples will be obtained from patients undergoing valve replacement, while healthy tissues will be obtained from cadavers. Immunohistology, proteomics, metabolomics, and transcriptome analyses will be used to analyse circulatory- and tissue-specific biomarkers. Univariate and multivariate statistical analyses will be used for hypothesis testing and identification of important biomarkers. In summary, this study aims to delineate the pathophysiology of RHD and degenerative AS using multiparametric CMR imaging. In addition to discover novel biomarkers and explore the pathomechanisms associated with RHD and AS through high-throughput profiling of the tissue and blood proteome and metabolome and provide a proof of concept of the suitability of using cadaveric tissues as controls for cardiovascular disease studies.

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“…However, hyperactivation of NRF2 led to the overexpression of p62, resulting in dysregulation of autophagy, and dysregulated p62 accumulation prolonged NRF2 activation, contributing to the pathological exacerbation of lung cancer and liver diseases [38][39][40][41]. There is growing evidence that dysregulation of autophagy, such as persistent or insufficient autophagy, can be detrimental to cells and tissues and lead to various human diseases [42][43][44][45].…”

Section: Introductionmentioning

confidence: 99%

TAZ deficiency impairs the autophagy-lysosomal pathway through NRF2 dysregulation and lysosomal dysfunction

Kim,

Jeong,

Jeong

et al. 2024

Int. J. Biol. Sci.

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Transcriptional coactivator with a PDZ-binding motif (TAZ) plays a key role in normal tissue homeostasis and tumorigenesis through interaction with several transcription factors. In particular, TAZ deficiency causes abnormal alveolarization and emphysema, and persistent TAZ overexpression contributes to lung cancer and pulmonary fibrosis, suggesting the possibility of a complex mechanism of TAZ function. Recent studies suggest that nuclear factor erythroid 2-related factor 2 (NRF2), an antioxidant defense system, induces TAZ expression during tumorigenesis and that TAZ also activates the NRF2-mediated antioxidant pathway. We thus thought to elucidate the cross-regulation of TAZ and NRF2 and the underlying molecular mechanisms and functions. TAZ directly interacted with NRF2 through the N-terminal domain and suppressed the transcriptional activity of NRF2 by preventing NRF2 from binding to DNA. In addition, the return of NRF2 to basal levels after signaling was inhibited in TAZ deficiency, resulting in sustained nuclear NRF2 levels and aberrantly increased expression of NRF2 targets. TAZ deficiency failed to modulate optimal NRF2 signaling and concomitantly impaired lysosomal acidification and lysosomal enzyme function, accumulating the abnormal autophagy vesicles and reactive oxygen species and causing protein oxidation and cellular damage in the lungs. TAZ restoration to TAZ deficiency normalized dysregulated NRF2 signaling and aberrant lysosomal function and triggered the normal autophagy-lysosomal pathway. Therefore, TAZ is indispensable for the optimal regulation of NRF2-mediated autophagy-lysosomal pathways and for preventing pulmonary damage caused by oxidative stress and oxidized proteins.

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Self-eating and Heart: The Emerging Roles of Autophagy in Calcific Aortic Valve Disease

Cited by 5 publications

References 175 publications

Extracellular vesicle miR-32 derived from macrophage promotes arterial calcification in mice with type 2 diabetes via inhibiting VSMC autophagy

Extracellular vesicle miR-32 derived from macrophage promotes arterial calcification in mice with type 2 diabetes via inhibiting VSMC autophagy

A study protocol to characterise pathophysiological and molecular markers of rheumatic heart disease and degenerative aortic stenosis using multiparametric cardiovascular imaging and multiomics techniques

TAZ deficiency impairs the autophagy-lysosomal pathway through NRF2 dysregulation and lysosomal dysfunction

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