Mitophagy acts as a safeguard mechanism against human vascular smooth muscle cell apoptosis induced by atherogenic lipids

Swiader, Audrey; Nahapetyan, Hripsime; Faccini, Julien; D'Angelo, Romina; Mucher, Elodie; Elbaz, Meyer; Boya, Patricia; Vindis, Cécile

doi:10.18632/oncotarget.8936

Cited by 99 publications

(83 citation statements)

References 44 publications

(67 reference statements)

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“…Since lipid efflux is closely related to reverse cholesterol transporters, including SR-B1, ATP-binding membrane cassette transport protein A1 (ABCA1) and G1 (ABCG1), 50 we further investigated whether these transporters were involved in the increased lipid efflux of macrophage induced by HY-SDT. As shown in Figure 6a, HY-SDT (2.5±0.3) significantly increased the expression level of ABCA1 compared with the control group (1.0±0.1), whereas it had no statistically significant effect on the expression levels of ABCG1 (1.2±0.2) or SR-B1 (1.1±0.2) compared with the control group (1.0±0.1 and 1.0±0.2 respectively).…”

Section: Resultsmentioning

confidence: 99%

“…31 Some researches show that autophagy has a protective role in human vascular smooth muscle cell and macrophage against apoptosis induced by atherogenic lipids. 30, 50 Although other studies indicate that autophagy promotes the elimination of damaged cells by apoptosis in cancer cells. 36 In this study, the results showed autophagy inhibition increased apoptosis following HY-SDT implying that HY-SDT-induced autophagy has antiapoptotic effect.…”

Section: Discussionmentioning

confidence: 99%

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Hypericin-mediated sonodynamic therapy induces autophagy and decreases lipids in THP-1 macrophage by promoting ROS-dependent nuclear translocation of TFEB

Zhang

Zheng

et al. 2016

Cell Death Dis

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Lipid catabolism disorder is the primary cause of atherosclerosis. Transcription factor EB (TFEB) prevents atherosclerosis by activating macrophage autophagy to promote lipid degradation. Hypericin-mediated sonodynamic therapy (HY-SDT) has been proved non-invasively inducing THP-1-derived macrophage apoptosis; however, it is unknown whether macrophage autophagy could be triggered by HY-SDT to influence cellular lipid catabolism via regulating TFEB. Here, we report that HY-SDT resulted in the time-dependent THP-1-derived macrophage autophagy activation through AMPK/AKT/mTOR pathway. Besides, TFEB nuclear translocation in macrophage was triggered by HY-SDT to promote autophagy activation and lysosome regeneration which enhanced lipid degradation in response to atherogenic lipid stressors. Moreover, following HY-SDT, the ABCA1 expression level was increased to promote lipid efflux in macrophage, and the expression levels of CD36 and SR-A were decreased to inhibit lipid uptake, both of which were prevented by TFEB knockdown. These results indicated that TFEB nuclear translocation activated by HY-SDT was not only the key regulator of autophagy activation and lysosome regeneration in macrophage to promote lipolysis, but also had a crucial role in reverse cholesterol transporters to decrease lipid uptake and increase lipid efflux. Reactive oxygen species (ROS) were adequately generated in macrophage by HY-SDT. Further, ROS scavenger N-acetyl-l-cysteine abolished HY-SDT-induced TFEB nuclear translocation and autophagy activation, implying that ROS were the primary upstream factors responsible for these effects during HY-SDT. In summary, our data indicate that HY-SDT decreases lipid content in macrophage by promoting ROS-dependent nuclear translocation of TFEB to influence consequent autophagy activation and cholesterol transporters. Thus, HY-SDT may be beneficial for atherosclerosis via TFEB regulation to ameliorate lipid overload in atherosclerotic plaques.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Hypericin-mediated sonodynamic therapy induces autophagy and decreases lipids in THP-1 macrophage by promoting ROS-dependent nuclear translocation of TFEB

Zhang

Zheng

et al. 2016

Cell Death Dis

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“…Recently, mitophagy plays an essential role in the regulation of VSMC functions, such as proliferation, migration and apoptosis (Swiader et al, ; Q. Zhao, Zhang, & Wang, ). In our study, we have reported that the Beclin‐1, LC3‐II/LC3‐I ratio are upregulated and that the level of p62 is downregulated during the process of apelin‐13‐induced human aortic VSMC proliferation.…”

Section: Discussionmentioning

confidence: 99%

PINK1/Parkin‐mediated mitophagy promotes apelin‐13‐induced vascular smooth muscle cell proliferation by AMPKα and exacerbates atherosclerotic lesions

Zhou

Huang

et al. 2018

Journal Cellular Physiology

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Aberrant proliferation of vascular smooth muscle cells (VSMC) is a critical contributor to the pathogenesis of atherosclerosis (AS). Our previous studies have demonstrated that apelin‐13/APJ confers a proliferative response in VSMC, however, its underlying mechanism remains elusive. In this study, we aimed to investigate the role of mitophagy in apelin‐13‐induced VSMC proliferation and atherosclerotic lesions in apolipoprotein E knockout (ApoE‐/‐) mice. Apelin‐13 enhances human aortic VSMC proliferation and proliferative regulator proliferating cell nuclear antigen expression in dose and time‐dependent manner, while is abolished by APJ antagonist F13A. We observe the engulfment of damage mitochondria by autophagosomes (mitophagy) of human aortic VSMC in apelin‐13 stimulation. Mechanistically, apelin‐13 increases p‐AMPKα and promotes mitophagic activity such as the LC3I to LC3II ratio, the increase of Beclin‐1 level and the decrease of p62 level. Importantly, the expressions of PINK1, Parkin, VDAC1, and Tom20 are induced by apelin‐13. Conversely, blockade of APJ by F13A abolishes these stimulatory effects. Human aortic VSMC transfected with AMPKα, PINK1, or Parkin and subjected to apelin‐13 impairs mitophagy and prevents proliferation. Additional, apelin‐13 not only increases the expression of Drp1 but also reduces the expressions of Mfn1, Mfn2, and OPA1. Remarkably, the mitochondrial division inhibitor‐1(Mdivi‐1), the pharmacological inhibition of Drp1, attenuates human aortic VSMC proliferation. Treatment of ApoE‐/‐ mice with apelin‐13 accelerates atherosclerotic lesions, increases p‐AMPKα and mitophagy in aortic wall in vivo. Finally, PINK1‐/‐ mutant mice with apelin‐13 attenuates atherosclerotic lesions along with defective in mitophagy. PINK1/Parkin‐mediated mitophagy promotes apelin‐13‐evoked human aortic VSMC proliferation by activating p‐AMPKα and exacerbates the progression of atherosclerotic lesions.

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“…As oxidative stress is elevated in diabetic and injury models, DRP1 inhibition may require the presence of certain stress levels in order to attenuate disease pathology in murine cardiovascular models. Oxidized low density lipoprotein enhances SMC but suppresses osteoblast differentiation, increases cellular oxidative stress 35 , and induces DRP1 mediated mitochondrial fission in SMCs 14 . A recent study found that treating rat SMCs with the antioxidant flavonoid Quercetin reduced DRP1 abundance and phosphate induced calcification in an oxidative stress dependent manner in vitro, along with suppressing calcification in adenine fed rats 66 , a model of chronic kidney disease.…”

Section: Discussionmentioning

confidence: 99%

“…No mechanism has been suggested for the presence of cardiac calcification in these mice, and whether DRP1 regulates calcification of other tissues, including the vasculature is unknown. DRP1inhibition prevents rat vascular neointima formation in a balloon injury model 12 , suppresses lesion formation in diabetic ApoE -deficient mice 13 , and oxidized low density lipoprotein induces DRP1 mediated mitochondrial fragmentation in human SMCs 14 , suggesting a possible role of DRP1 in vascular disease. Reduced mitochondrial fusion protein, Mitofusin 2 (MFN2) that acts in an opposite function to that of DRP1 driven mitochondrial fission, is associated with atherosclerosis pathology in mice 15, 16 , rabbits 17 , and humans 16 .…”

Section: Introductionmentioning

confidence: 99%

Dynamin-Related Protein 1 Inhibition Attenuates Cardiovascular Calcification in the Presence of Oxidative Stress

Rogers

Maldonado

Hutcheson

et al. 2017

Circulation Research

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Rationale Mitochondrial changes occur during cell differentiation and cardiovascular disease. Dynamin-related protein 1 (DRP1) is a key regulator of mitochondrial fission. We hypothesized that DRP1 plays a role in cardiovascular calcification, a process involving cell differentiation and a major clinical problem with high unmet needs. Objective To examine the effects of osteogenic promoting conditions on DRP1, and whether DRP1 inhibition alters the development of cardiovascular calcification. Methods and Results DRP1 was enriched in calcified regions of human carotid arteries, examined by immunohistochemistry. Osteogenic differentiation of primary human vascular smooth muscle cells (SMCs) increased DRP1 expression. DRP1 inhibition in human SMCs undergoing osteogenic differentiation attenuated matrix mineralization, cytoskeletal rearrangement, mitochondrial dysfunction, and reduced type 1 collagen secretion and alkaline phosphatase activity. DRP1 protein was observed in calcified human aortic valves, and DRP1 RNA interference reduced primary human valve interstitial cell calcification. Mice heterozygous for Drp1 deletion did not exhibit altered vascular pathology in a PCSK9 gain-of-function atherosclerosis model. However, when mineralization was induced via oxidative stress, DRP1 inhibition attenuated mouse and human SMC calcification. Femur bone density was unchanged in mice heterozygous for Drp1 deletion, and DRP1 inhibition attenuated oxidative stress-mediated dysfunction in human bone osteoblasts. Conclusions We demonstrate a new function of DRP1 in regulating collagen secretion and cardiovascular calcification, a novel area of exploration for the potential development of new therapies to modify cellular fibrocalcific response in cardiovascular diseases. Our data also support a role of mitochondrial dynamics in regulating oxidative stress-mediated arterial calcium accrual and bone loss.

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Mitophagy acts as a safeguard mechanism against human vascular smooth muscle cell apoptosis induced by atherogenic lipids

Cited by 99 publications

References 44 publications

Hypericin-mediated sonodynamic therapy induces autophagy and decreases lipids in THP-1 macrophage by promoting ROS-dependent nuclear translocation of TFEB

Hypericin-mediated sonodynamic therapy induces autophagy and decreases lipids in THP-1 macrophage by promoting ROS-dependent nuclear translocation of TFEB

PINK1/Parkin‐mediated mitophagy promotes apelin‐13‐induced vascular smooth muscle cell proliferation by AMPKα and exacerbates atherosclerotic lesions

Dynamin-Related Protein 1 Inhibition Attenuates Cardiovascular Calcification in the Presence of Oxidative Stress

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