AKT2 Confers Protection Against Aortic Aneurysms and Dissections

Shen, Ying H.; Zhang, Lin; Ren, Pingping; Nguyen, Mary; Zou, Sili; Wu, Danli; Wang, Xing Li; Coselli, Joseph S.; LeMaire, Scott A.

doi:10.1161/circresaha.112.300735

Cited by 82 publications

(90 citation statements)

References 60 publications

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“…PI3Kγ, the molecule upstream of Akt, was proved to inhibit the expression and activity of MMP-2 and MT1-MMP induced by biomechanical stress (Guo et al 2010). Akt2 inhibited MMP-9 expression while stimulated TIMP-1 expression by enhancing phosphorylation of FoxO1 in cultured VSMCs (Shen et al 2013). Furthermore, they found that there were FoxO1a binding sites in MMP-9 and TIMP-1 promoters.…”

Section: Discussionmentioning

confidence: 97%

Testosterone delays vascular smooth muscle cell senescence and inhibits collagen synthesis via the Gas6/Axl signaling pathway

Chen

Zhao

Jin

et al. 2016

AGE

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Testosterone deficiency is associated with a higher incidence of cardiovascular diseases in men. However, its effect on cell senescence, which plays a causal role in vascular aging, remains unclear. Here, we tested the hypothesis that testosterone alleviated vascular smooth muscle cell (VSMC) senescence and collagen synthesis via growth arrest-specific protein 6 (Gas6)/Axl-and Akt/FoxO1a-dependent pathways. Testosterone significantly ameliorated angiotensin IIinduced VSMC senescence and collagen overexpression. In addition, testosterone inhibited angiotensin IIinduced matrix metalloproteinase-2 (MMP-2) activity, which played a pivotal role in facilitating age-related collagen deposition. Testosterone increased the expression of tissue inhibitor of metalloproteinase-2 but decreased the expression of MMP-2 and membrane type-1 metalloproteinase which contributed to increase MMP-2 activity. The effects on VSMCs senescence and collagen synthesis were mediated by restoration of angiotensin II-induced downregulation of Gas6 and Axl expression and a subsequent reduction of Akt and FoxO1a phosphorylation. The effects of testosterone were reversed by a Gas6 blocker, AxlFc, and a specific inhibitor of Axl, R428. Treatment of VSMCs with PI3K inhibitor LY294002 abrogated the downregulating effect of testosterone on MMP-2 activity. Furthermore, when FoxO1a expression was silenced by using a specific siRNA, the inhibitory effect of testosterone on MMP-2 activity was revered as well, that indicated this process was Akt/FoxO1a dependence. Taken together, Gas6/Axl and Akt/ FoxO1a were involved in protective effects of testosterone on VSMCs senescence and collagen synthesis. Our results provide a novel mechanism underlying the protective effect of testosterone on vascular aging and may serve as a theoretical basis for testosterone replacement therapy.

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Section: Discussionmentioning

confidence: 97%

Testosterone delays vascular smooth muscle cell senescence and inhibits collagen synthesis via the Gas6/Axl signaling pathway

Chen

Zhao

Jin

et al. 2016

AGE

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“…11,20,21 In BAPN/Ang II-treated mice, neutrophils infiltrate the aortic intima, invariably triggering aortic dissection via metalloproteinase-9 production. 12 The sequence of events leading to aortic dissection in this model may well reflect those that underly a similar aortic pathology in humans.…”

Section: Discussionmentioning

confidence: 99%

Adventitial CXCL1/G-CSF Expression in Response to Acute Aortic Dissection Triggers Local Neutrophil Recruitment and Activation Leading to Aortic Rupture

Anzai

Shimoda

Endo

et al. 2015

Circulation Research

167

129

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A n acute aortic dissection (AAD) is initiated by an intimal tear, with resultant propagation within the middle third of the medial layer of the aorta. 1 To delineate treatment, the Stanford classification divides AAD into 2 types, type A and type B. Type A affects the ascending aorta, whereas type B does not. Type A AAD is more severe because of the higher mortality rate of 20% by 24 hours, 30% by 48 hours, 40% at 1 week, and 50% at 1 month.2 Thus, surgical repair is the first choice of treatment for patients with type A AAD to prevent life-threatening complications, including aortic rupture and cardiac tamponade. Although type B AAD is generally more benign and medical treatment for high blood pressure and intolerant pain can improve the patient's clinical outcome, a substantial proportion of medically treated patients still encounter catastrophic events within 7 days, such as aortic expansion and subsequent aortic rupture, visceral ischemia, and lung oxygenation impairment.2,3 Thoracic endovascular repair with stent grafting is the emerging therapeutic strategy Methods and Results:

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“…21 However, the expression and activation of Akt were prohibited in human aortic aneurysmal tissues and knockout of Akt-2 deteriorated Ang II-induced AAA. 22 NF-κB is an important transcriptional factor that mediates the expression of many proinflammatory cytokines and can be activated by Ang II. In this study, mediating these effects.…”

Section: Discussionmentioning

confidence: 99%

Dose-Dependent Bidirectional Effect of Angiotensin IV on Abdominal Aortic Aneurysm via Variable Angiotensin Receptor Stimulation

et al. 2015

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Angiotensin IV (Ang IV), as an effector peptide of the rennin–angiotensin system, possesses many biological properties yet not completely known. In this study, we aimed to investigate the role of Ang IV in the development of Ang II–induced abdominal aortic aneurysm (AAA) in apolipoprotein E-knockout mice. We used Ang II infusion to induce AAA, and animals were treated with Ang II (1.44 mg/kg per day) plus no treatment, Ang II (1.44 mg/kg per day) plus low-, medium-, and high-dose Ang IV (0.72, 1.44, and 2.88 mg/kg per day, respectively). The incidence of AAA was 87.5%, 66.7%, 37.5%, and 83.3% in the no treatment, the low-, medium-, or high-dose Ang IV group, respectively. Compared with the no treatment group, medium-dose Ang IV treatment markedly reduced macrophage infiltration; levels of proinflammatory cytokines, including monocyte chemoattractant protein 1, interleukin 6, and intercellular adhesion molecule 1; the expression and activity of metalloproteinases 2 and 9; but increased smooth muscle cells, and collagen content in AAA. However, high-dose Ang IV treatment did not have obvious protective effect. The beneficial effect of medium-dose Ang IV may be contributed to the stimulation of type 4 angiotensin receptor (AT 4 R) and AT 2 R with suppression of AT 1 R, activation of Akt, and inhibition of nuclear factor-κB, as these beneficial effects were largely reversed by cotreatment with the AT 4 R antagonist divalinal-Ang IV in Ang II–infused mice or with the Akt inhibitor A6730 in Ang II–stimulated human smooth muscle cells. Therefore, medium dose of Ang IV may provide a novel and promising approach to the treatment of AAA.

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AKT2 Confers Protection Against Aortic Aneurysms and Dissections

Cited by 82 publications

References 60 publications

Testosterone delays vascular smooth muscle cell senescence and inhibits collagen synthesis via the Gas6/Axl signaling pathway

Testosterone delays vascular smooth muscle cell senescence and inhibits collagen synthesis via the Gas6/Axl signaling pathway

Adventitial CXCL1/G-CSF Expression in Response to Acute Aortic Dissection Triggers Local Neutrophil Recruitment and Activation Leading to Aortic Rupture

Dose-Dependent Bidirectional Effect of Angiotensin IV on Abdominal Aortic Aneurysm via Variable Angiotensin Receptor Stimulation

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