The Potential Role of Kallistatin in the Development of Abdominal Aortic Aneurysm

Abstract

Abdominal aortic aneurysm (AAA) is a vascular condition that causes permanent dilation of the abdominal aorta, which can lead to death due to aortic rupture. The only treatment for AAA is surgical repair, and there is no current drug treatment for AAA. Aortic inflammation, vascular smooth muscle cell apoptosis, angiogenesis, oxidative stress and vascular remodeling are implicated in AAA pathogenesis. Kallistatin is a serine proteinase inhibitor, which has been shown to have a variety of functions, potentially relevant in AAA pathogenesis. Kallistatin has been reported to have inhibitory effects on tumor necrosis factor alpha (TNF-α) signaling induced oxidative stress and apoptosis. Kallistatin also inhibits vascular endothelial growth factor (VEGF) and Wnt canonical signaling, which promote inflammation, angiogenesis, and vascular remodeling in various pre-clinical experimental models. This review explores the potential protective role of kallistatin in AAA pathogenesis.

Keywords: abdominal aortic aneurysm; kallistatin; oxidative stress; serine proteinase inhibitors; vascular remodelling.

Figure 1

Kallistatin inhibits oxidative stress, inflammation and apoptosis through inhibiting TNF-α signaling and promotes NO production through eNOS stimulation. Kallistatin blocks TNF-α signaling through competitive binding to TNFR. This inhibits downstream signaling pathways that are activated by TNF-α, such as IκB/NF-κB and p38 MAPK pathway, which activate many pro-inflammatory and pro-angiogenic markers, such as TNF-α, VEGF, interleukins, MCP-1, MMPs and adhesion molecules. Kallistatin also inhibits TNF-α induces oxidative stress and the caspase cascade to induce apoptosis through TNFR-1. Alternatively, kallistatin is able to directly inhibit NADPH oxidase activity to attenuate ROS production, as well as activating eNOS through KLF4 to produce NO, which neutralizes ROS [43]. Abbreviations: endo-PC-endothelial progenitor cell, HUVEC-human umbilical vein endothelial cell, TNF-α-tumor necrosis factor alpha. Abbreviations: Akt/PKB—protein kinase B; ATF1—activating transcription factor 1; Bim—Bcl2 binding protein; eNOS—endothelial nitric oxide synthase; IκB—inhibitor of nuclear factor κ B; IKK—IκB kinase; JNK—c-Jun N-terminal kinase; KLF4—kruppel like factor 4; MAPK—mitogen activated protein kinase; MKK—MAPK kinase; NADPH—nicotinamide adenine dinucleotide phosphate; NF-κB—nuclear factor κB; NO—nitric oxide; P—phosphorylation; PI3K—phosphoinositide 3 kinase; ROS—reactive oxygen species; TNF-α—tumor necrosis factor alpha; TNFR—TNF-α receptor. The blue arrow lines indicate promotional activity; the red stop lines indicate inhibiting activity; the red dashed cross indicates degradation.

Figure 2

Kallistatin inhibits angiogenesis and inflammation through blocking VEGF signaling and NADPH oxidase activity. Kallistatin inhibits VEGF signaling through VEGFR-2 by its heparin-binding domain. VEGF-VEGFR signaling through PI3K-Akt pathway; the p38 MAPK pathway; and the PLC pathway leads to ROS/NO production, apoptosis, gene expression, cell migration, cell proliferation and inflammation. All of which are involved in angiogenesis. Kallistatin also directly inhibits NADPH oxidase activity and attenuates ROS production. NADPH oxidase is a complex consisting of several components. NADPH activity and VEGF-A/VEGFR-2 signaling have close interaction that is able to induce or activate many proangiogenic factors, such as MCP-1, VEGF, NF-κB, IL-8, VCAM-1, VE-cadherin and HIF1α in endothelial cells. Abbreviations: Akt—also known as protein kinase B—PKB; DAG—diacylglycerol; ERK—extracellular signal-regulated kinase; eNOS—endothelial nitric oxide synthase; HIF1α—hypoxia induced factor 1 alpha; IκB—inhibitor of nuclear factor κB; IL-8—interleukin-8; MAPK/MEK—mitogen activated protein kinase; MCP-1—monocyte chemoattractant protein-1; NADPH—nicotinamide adenine dinucleotide phosphate; NF-κB—nuclear factor κ B; NO—nitric oxide; PDK1/2—3-phosphoinositide dependent protein kinase 1 and 2; PI3K—phosphatidylinositol-3 kinase; PIP2—phosphatidylinositol 4,5-bisphosphate; PKC—protein kinase C; PLC—phospholipase C; PTP—protein tyrosine phosphatase; Rac1—small GTPase; ROS—reactive oxygen species; SOD—manganese superoxide dismutase; Src—non-receptor tyrosine kinase; VCAM-1—vascular cell adhesion molecule-1; VE—vascular endothelial; VEGF-A—vascular endothelial growth factor-A; VEGFR-2—VEGF receptor-2. The blue arrow lines indicate promotional activity; the red stop lines indicate inhibiting activity.

Figure 3

Kallistatin inhibits Wnt canonical pathway induced angiogenesis and inflammation. In the Wnt canonical pathways, mostly mediated by Wnt1, 3, 3a, 7a and 7b, Wnt/Fzd binding phosphorylates the associated co-receptor LRP5/6. This recruits Dsh which leads to binding of Axin at the membrane. Axin forms a degradation complex with APC, CK1α and GSK3β for β-catenin degradation. The recruitment binding of Axin to the membrane caused by Wnt/Fzd leads to an inactive degradation complex and the accumulation of β-catenin. The accumulated β-catenin mediates Wnt signaling by activating transcription factors, such as TCF, which induces transcription of genes, such as VEGF, ICAM-1 and TNF-α. Kallistatin binds to LRP6 and prevents LRP6 from phosphorylation which results in β-catenin degradation. Without β-catenin, Wnt canonical signaling is blocked. Abbreviation: AP-1—activator protein-1; APC—adenomatous polyposis coli; CAMKII—calmodulin dependent protein kinase; CK1α—casein kinase 1α; Dsh—the protein disheveled; GSK3β—glycogen synthase kinase-3β; ICAM-1—intracellulcar adhesion molecule-1; LRP5/6—low density lipoprotein receptor-related protein 5 or 6; PCP—planar cell polarity; OPG—osteoprotegerin; OPN—osteopontin; TCF—T-cell factor; TNF-α—tumor necrosis factor alpha; VEGF—vascular endothelial growth factor; the red arrow indicates increase in level; the tubular structure on the left represents cytoskeleton. The blue arrow lines indicate promotional activity; the red stop lines indicate inhibiting activity; the red dashed cross indicates degradation.

Figure 4

Illustration of postulated mechanisms of kallistatin attenuating AAA. Kallistatin has the potential of inhibiting various mechanisms that contribute to AAA formation. The pathological processes that are attenuated by kallistatin include oxidative stress, ROS signaling, apoptosis, angiogenesis, inflammation and MMP activity. The proposed AAA protective role of kallistatin are through its ability to inhibit various pathways, such as TNF-α, VEGF and Wnt canonical signaling pathways, as well as kallistatin’s ability to increase NO production through eNOS. The black arrow lines indicate promotional activity; the red stop lines indicate inhibiting activity.