1.αvβ3 Integrins Mediate Flow-Induced NF-κB Activation, Proinflammatory Gene Expression, and Early Atherogenic Inflammation.
Chen J1, Green J1, Yurdagul A Jr2, Albert P1, McInnis MC1, Orr AW3. Am J Pathol. 2015 Sep;185(9):2575-89. doi: 10.1016/j.ajpath.2015.05.013. Epub 2015 Jul 26.
Endothelial cell interactions with transitional matrix proteins, such as fibronectin, occur early during atherogenesis and regulate shear stress-induced endothelial cell activation. Multiple endothelial cell integrins bind transitional matrix proteins, including α5β1, αvβ3, and αvβ5. However, the role these integrins play in mediating shear stress-induced endothelial cell activation remains unclear. Therefore, we sought to elucidate which integrin heterodimers mediate shear stress-induced endothelial cell activation and early atherogenesis. We now show that inhibiting αvβ3 integrins (S247, siRNA), but not α5β1 or αvβ5, blunts shear stress-induced proinflammatory signaling (NF-κB, p21-activated kinase) and gene expression (ICAM1, VCAM1). Importantly, inhibiting αvβ3 did not affect cytokine-induced proinflammatory responses or inhibit all shear stress-induced signaling, because Akt, endothelial nitric oxide synthase, and extracellular regulated kinase activation remained intact.
2.Pharmacology of the novel antiangiogenic peptide ATN-161 (Ac-PHSCN-NH2): observation of a U-shaped dose-response curve in several preclinical models of angiogenesis and tumor growth.
Doñate F1, Parry GC, Shaked Y, Hensley H, Guan X, Beck I, Tel-Tsur Z, Plunkett ML, Manuia M, Shaw DE, Kerbel RS, Mazar AP. Clin Cancer Res. 2008 Apr 1;14(7):2137-44. doi: 10.1158/1078-0432.CCR-07-4530.
PURPOSE: ATN-161 (Ac-PHSCN-NH(2)) is an integrin-binding peptide that is currently in phase II trials in cancer patients. This peptide has been shown to have antitumor activity in a number of different preclinical models.
3.α5β1 integrin signaling mediates oxidized low-density lipoprotein-induced inflammation and early atherosclerosis.
Yurdagul A Jr1, Green J1, Albert P1, McInnis MC1, Mazar AP1, Orr AW2. Arterioscler Thromb Vasc Biol. 2014 Jul;34(7):1362-73. doi: 10.1161/ATVBAHA.114.303863. Epub 2014 May 15.
OBJECTIVE: Endothelial cell activation drives early atherosclerotic plaque formation. Both fibronectin deposition and accumulation of oxidized low-density lipoprotein (oxLDL) occur early during atherogenesis, and both are implicated in enhanced endothelial cell activation. However, interplay between these responses has not been established. The objective of our study was to determine whether endothelial matrix composition modulates the inflammatory properties of oxLDL.
4.Potential relevance of bell-shaped and u-shaped dose-responses for the therapeutic targeting of angiogenesis in cancer.
Reynolds AR1. Dose Response. 2010 Apr 23;8(3):253-84. doi: 10.2203/dose-response.09-049.Reynolds.
Tumor angiogenesis, the growth of new blood vessels into tumors, facilitates tumor growth and thus represents an attractive therapeutic target. Numerous experimental angiogenesis inhibitors have been characterised and subsequently trialled in patients. Some of these agents have failed to show any substantial activity in patients. In contrast, others have been more successful, but even these provide only a few months extra patient survival. Recent work has focused on understanding the effects of anti-angiogenic agents on tumor biology and has revealed a number of new findings that may help to explain the limited efficacy of angiogenesis inhibitors. Herein, I review the evidence that hormetic dose-responses (i.e. bell-shaped and U-shaped dose-response curves) are often observed with anti-angiogenic agents. Agents reported to exhibit these types of dose-response include: 5-fluorouracil, ATN-161, bortezomib, cisplatin, endostatin, enterostatin, integrin inhibitors, interferon-α, plasminogen activator-1 (PAI-1), rapamycin, rosiglitazone, statins, thrombospondin-1, TGF-α1 and TGF-α3.
