Angiotensin II-Regulated Autophagy Is Required for Vascular Smooth Muscle Cell Hypertrophy

Mondaca‐Ruff, David; Riquelme, Jaime A.; Quiroga, Clara; Norambuena-Soto, Ignacio; Sanhueza–Olivares, Fernanda; Villar-Fincheira, Paulina; Hernández-Díaz, Tomás; Cancino-Arenas, Nicole; Martín, Alejandra San; Garcı́a, Lorena; Lavandero, Sergio; Chiong, Mario

doi:10.3389/fphar.2018.01553

Cited by 38 publications

(32 citation statements)

References 60 publications

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“…It has been reported that TLR4-induced ATG7/autophagy inhibits enterocyte migration via induction of RhoA-mediated actin stress fibers 59 . Another study by Mondaca-Ruff et al 60 showed that angiotensin II induces autophagy via the RhoA/ ROCK pathway to cause vascular smooth muscle cells (VSMC) hypertrophy. Thus, ATG7/autophagy can act both upstream and downstream of RhoA/ROCK pathway.…”

Section: Discussionmentioning

confidence: 99%

Autophagy protein ATG7 is a critical regulator of endothelial cell inflammation and permeability

Shadab

Millar

Slavin

et al. 2020

Sci Rep

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Endothelial cell (EC) inflammation and permeability are critical pathogenic mechanisms in many inflammatory conditions including acute lung injury. In this study, we investigated the role of ATG7, an essential autophagy regulator with no autophagy-unrelated functions, in the mechanism of EC inflammation and permeability. Knockdown of ATG7 using si-RNA significantly attenuated thrombin-induced expression of proinflammatory molecules such as IL-6, MCP-1, ICAM-1 and VCAM-1. Mechanistic study implicated reduced NF-κB activity in the inhibition of EC inflammation in ATG7silenced cells. Moreover, depletion of ATG7 markedly reduced the binding of RelA/p65 to DNA in the nucleus. Surprisingly, the thrombin-induced degradation of IκBα in the cytosol was not affected in ATG7-depleted cells, suggesting a defect in the translocation of released RelA/p65 to the nucleus in these cells. This is likely due to suppression of thrombin-induced phosphorylation and thereby inactivation of Cofilin1, an actin-depolymerizing protein, in ATG7-depleted cells. Actin stress fiber dynamics are required for thrombin-induced translocation of RelA/p65 to the nucleus, and indeed our results showed that ATG7 silencing inhibited this response via inactivation of Cofilin1. ATG7 silencing also reduced thrombin-mediated EC permeability by inhibiting the disassembly of VE-cadherin at adherens junctions. Together, these data uncover a novel function of ATG7 in mediating EC inflammation and permeability, and provide a mechanistic basis for the linkage between autophagy and EC dysfunction. Endothelial cell (EC) inflammation and permeability represent two major pathogenic features of many inflammatory conditions including acute lung injury (ALI) 1-3. ECs form the lining of the blood vessels of many organs such as the lung, heart, brain, kidney, and liver etc. Thus, ECs play an important role as a gate-keeper, preserving vascular integrity and providing a natural barrier to circulating blood, together maintaining homeostasis 4,5. Previous studies on EC inflammation and barrier function have shown that vascular EC exposed to bacterial, chemical, and mechanical insults secrete inflammatory and chemotactic molecules, and demonstrate loss of barrier integrity 6. Among the major causes for the exhibition of such inflammation and barrier disruption include activation of the transcription factor NF-κB and disassembly of adherens junctions (AJs) 7,8. NF-κB is a ubiquitously expressed family of transcription factors which play important roles in various processes including inflammation, cell proliferation, differentiation, and survival 9,10. The NF-κB family is comprised of five members: Rel (c-Rel), Rel A (p65), Rel B, NF-κB1 (p105/p50), and NF-κB2 (p100/p52) 11,12. In inactive conditions NF-κB remains in the cytoplasm while bound to its inhibitory protein IκBα 9. During an inflammatory response, IκBα undergoes phosphorylation at Ser32 and Ser36 leading to its proteasome-mediated degradation and subsequent release of NF-κB (predominantly RelA/p65 homodimer in EC) 1...

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Section: Discussionmentioning

confidence: 99%

Autophagy protein ATG7 is a critical regulator of endothelial cell inflammation and permeability

Shadab

Millar

Slavin

et al. 2020

Sci Rep

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“…As a major component of the vessel wall, VSMCs are responsible for the control of blood ow and arterial pressure by regulating the lumen's diameter of resistance vessels in response to Ang-II [20]. Ang-II induced autophagy by increasing Beclin-1, Vps34, Atg-12-Atg5, Atg4 and Atg7 protein levels, Beclin-1 phosphorylation, and the number of autophagic vesicles [21]. Here, we found that Atg7 was up-regulated in Ang-II treated VSMCs, as our previous study showed that metformin represses the pathophysiology of AAA by inhibiting autophagy pathway [15], in this study, we showed that the induced expression of Atg7 in AAA was reversed by metformin.…”

Section: Discussionmentioning

confidence: 99%

Atg7 Mediates Metformin Protected Abdominal Aortic Aneurysm by Inducing Autophagy

Guo

Wang

Xue

et al. 2020

Preprint

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BackgroundAbdominal aortic aneurysm (AAA) is pathologic dilation of the abdominal aorta and is often asymptomatic but has high susceptibility to rupture. Our previous study showed that metformin protected the pathophysiology of AAA by reducing the activation of PI3K/AKT/mTOR pathway. MethodsAngiotensin II (Ang-II) was used to construct the AAA model in vascular smooth muscle cells (VSMCs). The expression of Atg7 and Atg4 was determined by qRT-PCR and Western blot. Atg7 expression was regulated by overexpressed plasmid or siRNA to examine the cell proliferation, cell migration, cell apoptosis and autophagy caused by Ang-II. ResultsAng-II induced the expression of Atg7 and metformin reversed this effect. Suppression of Atg7 inhibited cell proliferation and cell migration, reduced cell apoptosis and autophagy, while overexpression of Atg7 enhanced cell proliferation and cell migration, induced cell apoptosis and autophagy. Moreover, the expression of autophagy related protein was regulated by Atg7 in Ang-II treated VSMCs. We further showed that the Atg7 mediated-autophagy was attenuated by metformin. ConclusionMetformin-reduced autophagy in AAA was mediated by Atg7, suggesting that Atg7 was a potential downstream effector of metformin in protecting the pathophysiology of AAA.

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“…Later, LC3 I forms a conjugate with phosphatidylethanolamine (PE) by the transforming action of ATG7 and ATG3, thereby generating LC3 II. LC3 II then attaches to the autophagosome membrane triggering its elongation ( Mondaca-Ruff et al, 2018 ). The lysosomal proteolytic enzyme Cathepsin D is the only aspartic-type protease that is ubiquitously found in every cell of the human body.…”

Section: Introductionmentioning

confidence: 99%

Notoginsenoside R1 Protects Against the Acrylamide-Induced Neurotoxicity via Upregulating Trx-1-Mediated ITGAV Expression: Involvement of Autophagy

Wang

Thomas

et al. 2020

Front. Pharmacol.

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Acrylamide (ACR) is a common chemical used in various industries and it said to have chronic neurotoxic effects. It is produced during tobacco smoking and is also generated in high-starch foods during heat processing. Notoginsenoside R1 (NR1) is a traditional Chinese medicine, which is used to improve the blood circulation and clotting. The objective of this study was to investigate the mechanism of ACR-triggered neurotoxicity and to identify the protective role of NR1 by upregulating thioredoxin-1 (Trx-1). Our results have shown that NR1 could block the spatial and cognitive impairment caused by ACR administration. Bioinformatics analysis revealed that Trx-1 regulated autophagy via Integrin alpha V (ITGAV). NR1 could resist the ACR-induced neurotoxicity by upregulating thioredoxin-1 in PC12 cells and mice. The autophagy-related proteins like autophagy-related gene (ATG) 4B, Cathepsin D, LC3 II, lysosomal-associated membrane protein 2a (LAMP2a), and ITGAV were restored to normal levels by NR1 treatment in both PC12 cells and mice. Besides, we also found that overexpression of Trx-1 resisted ACR-induced autophagy in PC12 cells and downregulation of Trx-1 triggered autophagy induced by ACR in PC12 cells. Therefore, it could be concluded that Trx-1 was involved in the autophagy pathway. Besides, we also found that ITGAV was an intermediate node linking Trx-1 and the autophagy pathway.

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Angiotensin II-Regulated Autophagy Is Required for Vascular Smooth Muscle Cell Hypertrophy

Cited by 38 publications

References 60 publications

Autophagy protein ATG7 is a critical regulator of endothelial cell inflammation and permeability

Autophagy protein ATG7 is a critical regulator of endothelial cell inflammation and permeability

Atg7 Mediates Metformin Protected Abdominal Aortic Aneurysm by Inducing Autophagy

Notoginsenoside R1 Protects Against the Acrylamide-Induced Neurotoxicity via Upregulating Trx-1-Mediated ITGAV Expression: Involvement of Autophagy

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