Kallistatin is a potent new vasodilator.

Chao, Julie; Stallone, John N.; Liang, Yu Mei; Chen, L M; Wang, D Z; Chao, Lee

doi:10.1172/jci119502

Cited by 79 publications

(66 citation statements)

References 21 publications

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“…Our previous study showed specific kallistatin-binding sites in rat aortic membrane proteins by Scatchard plot analysis, indicating potential kallistatin receptor(s) in mediating the vascular function of kallistatin (3). Kallistatin exhibits pleiotropic effects in inhibiting apoptosis, inflammation, and fibrosis in cardiac, renal, and vascular cells (6,7,12).…”

Section: Discussionmentioning

confidence: 98%

“…Recent studies indicate that kallistatin exerts pleiotropic effects such as vasodilation and inhibition of angiogenesis, tumor growth, inflammation, and oxidative stress, independent of tissue kallikrein (3)(4)(5)(6)(7). We showed that an intravenous bolus injection of human kallistatin caused a rapid and transient reduction of mean arterial blood pressure in anesthetized rats and that kallistatin induced relaxation in isolated aorta rings (3).…”

mentioning

confidence: 79%

“…We showed that an intravenous bolus injection of human kallistatin caused a rapid and transient reduction of mean arterial blood pressure in anesthetized rats and that kallistatin induced relaxation in isolated aorta rings (3). Moreover, a high affinity binding site for kallistatin was identified in the aortic membrane using 125 Ilabeled kallistatin (3). Furthermore, kallistatin directly stimulated the proliferation and migration of cultured vascular smooth muscle cells by activating mitogen-activated protein kinases (8).…”

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confidence: 99%

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Kruppel-like Factor 4 Is a Novel Mediator of Kallistatin in Inhibiting Endothelial Inflammation via Increased Endothelial Nitric-oxide Synthase Expression

Shen

Smith

Hsu

et al. 2009

Journal of Biological Chemistry

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Kallistatin is a plasma protein that exhibits pleiotropic effects in vasodilation, anti-angiogenesis, and anti-inflammation. To isolate a kallistatin-binding protein that mediates the vascular actions of kallistatin, we screened and identified a positive clone from a human heart cDNA expression library by using an alkaline phosphatase-kallistatin fusion protein binding assay. Sequence analysis revealed that kallistatin-binding protein is human Kruppel-like factor 4 (KLF4). KLF4 was localized on the plasma membrane of HEK-293 cells and endothelial cells overexpressing KLF4. KLF4 and kallistatin complex formation was identified in endothelial cells by immunoprecipitation followed by immunoblotting. We showed that kallistatin inhibits tumor necrosis factor-␣-induced NF-B activation, as well as vascular cell adhesion molecule-1 and monocyte chemoattractant protein-1 expression in endothelial cells, whereas knockdown of KLF4 by small interfering RNA oligonucleotide abolished the effect of kallistatin. Kallistatin increased endothelial nitric-oxide synthase (eNOS) expression and nitric oxide levels, and these effects were also blocked by KLF4 small interfering RNA oligonucleotide. Moreover, inhibition of eNOS by RNA interference or by NOS inhibitor abolished the blocking effect of kallistatin on vascular cell adhesion molecule-1 and monocyte chemoattractant protein-1 expression. In summary, we identified KLF4 as a kallistatin-binding protein, which has a novel role in mediating the anti-inflammatory actions of kallistatin via increasing eNOS expression in endothelial cells. This study provides a new target for modulating endothelial function in vascular disease.Kallistatin was discovered as a tissue kallikrein inhibitor from human plasma (1, 2). Recent studies indicate that kallistatin exerts pleiotropic effects such as vasodilation and inhibition of angiogenesis, tumor growth, inflammation, and oxidative stress, independent of tissue kallikrein (3-7). We showed that an intravenous bolus injection of human kallistatin caused a rapid and transient reduction of mean arterial blood pressure in anesthetized rats and that kallistatin induced relaxation in isolated aorta rings (3). Moreover, a high affinity binding site for kallistatin was identified in the aortic membrane using 125 Ilabeled kallistatin (3). Furthermore, kallistatin directly stimulated the proliferation and migration of cultured vascular smooth muscle cells by activating mitogen-activated protein kinases (8). These findings suggest the presence of kallistatin receptors or binding proteins that mediate its effects in the vasculature. However, the identity of the kallistatin receptor/ binding protein has not been determined.Kallistatin is a negative acute-phase protein, which is reduced after acute lipopolysaccharide-induced inflammation and in chronic inflammatory disease (9). Transgenic mice overexpressing kallistatin are more resistant to lipopolysaccharideinduced lethality (10). Kallistatin administration via gene delivery significantly decreased neutroph...

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Section: Discussionmentioning

confidence: 98%

mentioning

confidence: 79%

mentioning

confidence: 99%

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Kruppel-like Factor 4 Is a Novel Mediator of Kallistatin in Inhibiting Endothelial Inflammation via Increased Endothelial Nitric-oxide Synthase Expression

Shen

Smith

Hsu

et al. 2009

Journal of Biological Chemistry

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“…8 Kallistatin is a member of the serine proteinase inhibitor (serpin) superfamily and was shown to have pleiotropic effects, including hypotension, anti-angiogenesis and antiinflammation. [9][10][11] Kallistatin gene delivery reduced ischemic myocardial inflammation and cardiomyocyte apoptosis at 1 day after acute ischemia/reperfusion injury. 12 Recently, we observed that increased oxidative stress after MI was associated with reduced circulating kallistatin levels, suggesting that kallistatin might be involved in the progression of oxidative cardiac damage.…”

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confidence: 99%

Role of kallistatin in prevention of cardiac remodeling after chronic myocardial infarction

Gao

Yin

Smith

et al. 2008

Laboratory Investigation

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Oxidative stress causes cardiomyocyte death and subsequent ventricular dysfunction and cardiac remodeling after myocardial infarction (MI), thus contributing to high mortality in chronic heart failure patients. We investigated the effects of kallistatin in cardiac remodeling in a chronic MI rat model and in primary cardiac cells. Human kallistatin gene was injected intramyocardially 20 min after ligation of the left coronary artery. At 4 weeks after MI, expression of human kallistatin in rat hearts was identified by reverse transcription-polymerase chain reaction, immunohistochemistry and ELISA. Kallistatin administration improved cardiac performance, increased mean arterial pressure, decreased myocardial infarct size and restored left ventricular wall thickness. Kallistatin treatment significantly attenuated cardiomyocyte size and atrial natriuretic peptide expression. Kallistatin also reduced collagen accumulation, collagen fraction volume and expression of collagen types I and III, transforming growth factor-b1 (TGF-b1) and plasminogen activator inhibitor-1 in the myocardium. Inhibition of cardiac hypertrophy and fibrosis by kallistatin was associated with increased cardiac nitric oxide (NO) levels and decreased superoxide formation, NADH oxidase activity and p22-phox expression. Moreover, in both primary cultured rat cardiomyocytes and myofibroblasts, recombinant kallistatin inhibited intracellular superoxide formation induced by H 2 O 2 , and the antioxidant effect of kallistatin was abolished by No-nitro-L-arginine methyl ester (L-NAME), indicating a NO-mediated event. Kallistatin promoted survival of cardiomyocytes subjected to H 2 O 2 treatment, and inhibited H 2 O 2 -induced Akt and ERK phosphorylation, as well as NF-kB activation. Furthermore, kallistatin abrogated TGF-b-induced collagen synthesis and secretion in cultured myofibroblasts. This is the first study to demonstrate that kallistatin improves cardiac performance and prevents post-MI-induced cardiac hypertrophy and fibrosis through its antioxidant action. Myocardial infarction (MI) leads to cardiac remodeling with complex structural alterations. After an ischemic insult, left ventricle (LV) enlargement is followed by progressive diastolic stiffness, enhanced wall stress and oxygen consumption, thus resulting in cardiomyocyte hypertrophy, interstitial fibrosis and decreased cardiac output. Increased reactive oxygen species (ROS) levels are recognized to be involved in ischemic heart failure and considered to be a major cause of cardiomyocyte death, ventricular dysfunction and heart failure progress. 1 Under pathological conditions, increased oxidative stress damages DNA and mitochondrial function, activates proapoptotic signaling kinases and leads to myocyte apoptosis or necrosis. 2,3 Elevation of ROS activates a series of hypertrophic signaling kinases and transcription factors to stimulate cardiac hypertrophy. 3,4 Moreover, ROS stimulate fibroblast proliferation and activate the expression of profibrotic factors, including transforming growth...

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“…Another explanation, as suggested by our previous study (19), is that the apparent up-regulated TK metabolic activity is a function of its preactivation and half-life (t 1/2 ). Cellular TK, stored as inactive prekallikrein, is usually activated to TK which has proteolytic functions both within the endothelial cell and in the extracellular environment, until it is sequestered by inhibitors such as kallikrein binding protein (KBP), Protein C and kallistatin, resulting in a t 1/2 of several hours (44)(45)(46). Our anti-TK IgG detected both the prekallikrein stored within unchallenged HUVECs as well as TK released from HUVECs following activation by cervical cancer cell metabolites.…”

Section: Discussionmentioning

confidence: 99%

Angiogenesis in cervical cancer is mediated by HeLa metabolites through endothelial cell tissue kallikrein

Naidoo

Raidoo²

2009

Oncol Rep

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Kallistatin is a potent new vasodilator.

Cited by 79 publications

References 21 publications

Kruppel-like Factor 4 Is a Novel Mediator of Kallistatin in Inhibiting Endothelial Inflammation via Increased Endothelial Nitric-oxide Synthase Expression

Kruppel-like Factor 4 Is a Novel Mediator of Kallistatin in Inhibiting Endothelial Inflammation via Increased Endothelial Nitric-oxide Synthase Expression

Role of kallistatin in prevention of cardiac remodeling after chronic myocardial infarction

Angiogenesis in cervical cancer is mediated by HeLa metabolites through endothelial cell tissue kallikrein

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