An anti-αVβ3 antibody inhibits coronary artery atherosclerosis in diabetic pigs

Maile, Laura A.; Busby, Walker H.; Xu, Gang; Gollahan, K.P.; Flowers, W. L.; Gafbacik, N.; Gafbacik, S.; Stewart, Kara R; Merricks, Elizabeth P.; Nichols, Timothy C.; Bellinger, Dwight A.; Clemmons, David R.

doi:10.1016/j.atherosclerosis.2017.01.030

Cited by 8 publications

(5 citation statements)

References 43 publications

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“…High glucose enhances MDM2-mediated ubiquitination of p53, which down-regulates p53, but IRS-1 overexpression inhibits the p53/MDM2 interaction and p53 ubiquitination, thereby stabilizing p53 and promoting p53/ KLF4-mediated induction of differentiation during chronic hyperglycemia. Although diabetic mice have signaling abnormalities that are present in atherosclerotic vessels, they do not develop lesions in the absence of hyperlipidemia; therefore, we analyzed arterial tissue obtained from diabetic pigs that develop extensive lesions (18). The results showed that p53 and IRS-1…”

Section: Irs-1 Maintains Vsmc Differentiationmentioning

confidence: 99%

“…Although VSMCs from diabetic mice undergo several changes in signaling that are similar to changes that occur in atherosclerotic lesions, they do not develop typical subintimal plaques unless they are also hyperlipidemic. To determine if the changes in p53, IRS-1, and KLF4 noted in our mice were present in an animal model that does develop subintimal lesions, we analyzed femoral arteries obtained from diabetic pigs that had been fed a high fat diet and had been shown to have extensive atherosclerosis (18). The results show that arterial extracts from the diabetic animals had a 2.6 Ϯ 0.1-fold reduction (p Ͻ 0.001) (n ϭ 5) in IRS-1 and a 2.8 Ϯ 0.1-fold decrease (p Ͻ 0.01) (n ϭ 5) in p53 compared with nondiabetic pigs (Fig.…”

Section: Irs-1 Maintains Vsmc Differentiationmentioning

confidence: 99%

“…Diabetes was induced in pigs using strepozotocin, and femoral artery extracts were prepared as described previously (18). The animals were diabetic for 6 months prior to analysis.…”

Section: Induction Of Diabetic Pigs and Preparation Of Femoral Arterymentioning

confidence: 99%

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Hyperglycemia induces vascular smooth muscle cell dedifferentiation by suppressing insulin receptor substrate-1–mediated p53/KLF4 complex stabilization

Shen

Wai

et al. 2019

Journal of Biological Chemistry

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Edited by Jeffrey E. PessinHyperglycemia and insulin resistance accelerate atherosclerosis by an unclear mechanism. The two factors down-regulate insulin receptor substrate-1 (IRS-1), an intermediary of the insulin/IGF-I signaling system. We previously reported that IRS-1 down-regulation leads to vascular smooth muscle cell (VSMC) dedifferentiation and that IRS-1 deletion from VSMCs in normoglycemic mice replicates this response. However, we did not determine IRS-1's role in mediating differentiation. Here, we sought to define the mechanism by which IRS-1 maintains VSMC differentiation. High glucose or IRS-1 knockdown decreased p53 levels by enhancing MDM2 proto-oncogene (MDM2)-mediated ubiquitination, resulting in decreased binding of p53 to Krüppel-like factor 4 (KLF4). Exposure to nutlin-3, which dissociates MDM2/p53, decreased p53 ubiquitination and enhanced the p53/KLF4 association and differentiation marker protein expression. IRS-1 overexpression in high glucose inhibited the MDM2/p53 association, leading to increased p53 and p53/KLF4 levels, thereby increasing differentiation. Nutlin-3 treatment of diabetic or Irs1 ؊/؊ mice enhanced p53/ KLF4 and the expression of p21, smooth muscle protein 22 (SM22), and myocardin and inhibited aortic VSMC proliferation. Injecting normoglycemic mice with a peptide disrupting the IRS-1/p53 association reduced p53, p53/KLF4, and differentiation. Analyzing atherosclerotic lesions in hypercholesterolemic, diabetic pigs, we found that p53, IRS-1, SM22, myocardin, and KLF4/p53 levels are significantly decreased compared with their expression in nondiabetic pigs. We conclude that IRS-1 is critical for maintaining VSMC differentiation. Hyperglycemia-or insulin resistance-induced IRS-1 down-regulation decreases the p53/KLF4 association and enhances dedifferentiation and proliferation. Our results suggest that enhancing IRS-1-dependent p53 stabilization could attenuate the progression of atherosclerotic lesions in hyperglycemia and insulin-resistance states. . 3 The abbreviations used are: IGF-I, insulin-like growth factor-I; IRS-1, insulin receptor substrate-1; Shc, Src homology 2 domain-containingtransforming protein C; VSMC, vascular smooth muscle cell; mSMC, mouse smooth muscle cell; pSMC, porcine smooth muscle cell; PI3K, phosphatidylinositol 3-kinase; NS, not significant; ID3, inhibitor of differentiation 3; NG, normal glucose; HG, high glucose; NHG, normal-high glucose transient exposure; i.p., intraperitoneally; DAPI, 4Ј,6-diamidino-2-phenylindole; WCL, whole-cell lysates; SM22, smooth muscle protein 22; MyoC, myocardin; DM, diabetic WT mice; NM, nondiabetic WT mice.

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Section: Irs-1 Maintains Vsmc Differentiationmentioning

confidence: 99%

Section: Irs-1 Maintains Vsmc Differentiationmentioning

confidence: 99%

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Hyperglycemia induces vascular smooth muscle cell dedifferentiation by suppressing insulin receptor substrate-1–mediated p53/KLF4 complex stabilization

Shen

Wai

et al. 2019

Journal of Biological Chemistry

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“…Evidence from diabetic aortic SMC suggests that the Kir subunits of the channel are not affected by diabetes, yet expression of the SUR2B subunit is markedly inhibited [56] . Unfortunately, the influence of diabetes and/or hyperglycaemia on Na + /K + ATPase activity varies according to species and vascular bed [57][58][59] , thus extrapolating a hypothesis on whether this pump is affected in coronary artery SMC is impossible. In terms of proliferation and adhesion to the extracellular matrix, recent studies have found marked reductions in the development of atherosclerosis in a diabetic porcine model when the animals are treated with an integrin α V β3 blocking antibody.…”

Section: Diabetes and Obesitymentioning

confidence: 99%

Phenotypic differences between microvascular and macrovascular smooth muscle cells and their contribution to coronary microvascular dysfunction

Riches-Suman¹

2021

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“…αvβ3 also plays a vital role in promoting platelet adhesion. Inhibiting αvβ3 can suppress inflammation and smooth muscle recruitment, thereby weakening atherosclerosis [66]. In order to clarify the specific role of αIIbβ3 in AS, it is necessary to use platelet-specific knockout β3 for in-depth research.…”

Section: Integrin αIibβ3mentioning

confidence: 99%

Targeting Platelet in Atherosclerosis Plaque Formation: Current Knowledge and Future Perspectives

Wang

Tang

2020

IJMS

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Besides their role in hemostasis and thrombosis, it has become increasingly clear that platelets are also involved in many other pathological processes of the vascular system, such as atherosclerotic plaque formation. Atherosclerosis is a chronic vascular inflammatory disease, which preferentially develops at sites under disturbed blood flow with low speeds and chaotic directions. Hyperglycemia, hyperlipidemia, and hypertension are all risk factors for atherosclerosis. When the vascular microenvironment changes, platelets can respond quickly to interact with endothelial cells and leukocytes, participating in atherosclerosis. This review discusses the important roles of platelets in the plaque formation under pro-atherogenic factors. Specifically, we discussed the platelet behaviors under disturbed flow, hyperglycemia, and hyperlipidemia conditions. We also summarized the molecular mechanisms involved in vascular inflammation during atherogenesis based on platelet receptors and secretion of inflammatory factors. Finally, we highlighted the studies of platelet migration in atherogenesis. In general, we elaborated an atherogenic role of platelets and the aspects that should be further studied in the future.

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An anti-αVβ3 antibody inhibits coronary artery atherosclerosis in diabetic pigs

Cited by 8 publications

References 43 publications

Hyperglycemia induces vascular smooth muscle cell dedifferentiation by suppressing insulin receptor substrate-1–mediated p53/KLF4 complex stabilization

Hyperglycemia induces vascular smooth muscle cell dedifferentiation by suppressing insulin receptor substrate-1–mediated p53/KLF4 complex stabilization

Phenotypic differences between microvascular and macrovascular smooth muscle cells and their contribution to coronary microvascular dysfunction

Targeting Platelet in Atherosclerosis Plaque Formation: Current Knowledge and Future Perspectives

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