Protective Role of Kallistatin in Vascular and Organ Injury

Abstract

Kallistatin is an endogenous protein that exerts pleiotropic effects, including vasodilation and inhibition of angiogenesis, inflammation, oxidative stress, apoptosis, fibrosis, and tumor progression. Through its two functional domains – an active site and a heparin-binding site – kallistatin regulates differential signaling pathways and a wide spectrum of biological functions. Kallistatin's active site is key for inhibiting tissue kallikrein activity, and stimulating the expression of endothelial nitric oxide synthase (eNOS), sirtuin 1 (SIRT1) and suppressor of cytokine signaling 3 (SOCS3). Kallistatin via its heparin-binding site blocks signaling pathways mediated by growth factors and cytokines, such as vascular endothelial growth factor (VEGF), tumor necrosis factor-α (TNF-α), high mobility group box-1 (HMGB1), Wnt, transforming growth factor-β (TGF-β), and epidermal growth factor (EGF). Kallistatin gene or protein delivery protects against the pathogenesis of hypertension, heart and kidney damage, arthritis, sepsis, influenza virus infection, tumor growth and metastasis in animal models. Conversely, depletion of endogenous kallistatin by neutralizing antibody injection exacerbates cardiovascular and renal injury in hypertensive rats. Kallistatin levels are markedly reduced in rodents with hypertension, sepsis, streptozotocin-induced diabetes, and cardiac and renal injury. Kallistatin levels are also diminished in patients with liver disease, septic syndrome, diabetic retinopathy, severe pneumonia, inflammatory bowel disease, and obesity, prostate and colon cancer. Therefore, circulating kallistatin levels may serve as a new biomarker for human diseases. This review summarizes kallistatin's protective roles and mechanisms in vascular and organ injury, and highlights the therapeutic potential of kallistatin for multiple disease states.

Fig. 1

Endogenous kallistatin plays a role in blood pressure regulation of normotensive Wistar rats, and kallistatin's active site is essential for stimulating vasodilation via NO production. Injection of anti-rat kallistatin antibody increases blood pressure as determined by (A) tail-cuff and (B) cannulation methods. (C) Both wild-type kallistatin (KS) and heparin-binding site mutant kallistatin (HMKS), but not active site mutant kallistatin (AMKS), induce vasodilation. (D) Kallistatin's vasodilatory action is blocked by the nitric oxide synthase inhibitor, L-NAME.

Fig. 2

Kallistatin, via its heparin-binding site and active site, protects against tumor growth and metastasis by blocking signaling pathways stimulated by vascular endothelial growth factor (VEGF), tumor necrosis factor (TNF)-α, high mobility group box-1 (HMGB1), Wnt, epidermal growth factor (EGF) and transforming growth factor (TGF)-β, and by inhibiting tissue kallikrein-mediated actions.

Fig. 3

Kallistatin, through its structural elements, exerts anti-inflammatory actions by antagonizing vascular endothelial growth factor (VEGF)-, tumor necrosis factor (TNF)-α-, and high mobility group box-1 (HMGB1)-mediated effects, and by inducing the expression of endothelial nitric oxide synthase (eNOS), sirtuin 1 (SIRT1) and suppressor of cytokine signaling 3 (SOCS3).

Fig. 4

Kallistatin, through its structural elements, exerts antioxidant actions by blocking tumor necrosis factor-α (TNF-α)- and transforming growth factor-β (TGF-β)-induced signaling, and stimulating endothelial nitric oxide synthase (eNOS) and sirtuin 1 (SIRT1) expression. Both eNOS and SIRT1 increase NO formation which, in turn, inhibits NAD(P)H oxidase. Moreover, FoxO1 activation by SIRT1 subsequently leads to superoxide dismutase 2 (SOD2) expression. Genistein, a tyrosine kinase inhibitor, blocks kallistatin's effects on eNOS, SIRT1 and FoxO1.