Protein kinase G increases antioxidant function in lung microvascular endothelial cells by inhibiting the c-Abl tyrosine kinase

Stephens, Robert S.; Servinsky, Laura; Rentsendorj, Otgonchimeg; Kolb, Todd M.; Pfeifer, Alexander; Pearse, David B.

doi:10.1152/ajpcell.00375.2012

Cited by 21 publications

(41 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Another study demonstrated the capability of imatinib to inhibit endothelial permeability induced by the inflammatory agents VEGF, thrombin, and histamine in human microvascular EC (11). Imatinib also protected against H 2 O 2 -induced increased permeability in an in vitro model of oxidative stress in mouse lung EC (57). Finally, a recent case report of a patient with systemic capillary leak syndrome described impressive reversal of vascular leak after imatinib treatment, suggesting the clinical potential of this approach (1).…”

Section: Discussionmentioning

confidence: 91%

“…We previously reported that c-Abl mediates enhancement of the lung EC barrier by the potent agonists S1P or FTY720 (20,59). In contrast, other reports indicate that c-Abl mediates oxidative stress-induced hyperpermeability (57,58), whereas Arg mediates EC barrier disruption induced by thrombin or VEGF (2). Additional studies support both similar and distinct roles for c-Abl and Arg kinases in other cellular processes relevant to barrier function including focal adhesion and cytoskeletal dynamics (48,62).…”

mentioning

confidence: 90%

See 1 more Smart Citation

Differential and opposing effects of imatinib on LPS- and ventilator-induced lung injury

Letsiou

Rizzo

Sammani

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

View full text Add to dashboard Cite

Endothelial dysfunction underlies the pathophysiology of vascular disorders such as acute lung injury (ALI) syndromes. Recent work has identified the Abl family kinases (c-Abl and Arg) as important regulators of endothelial cell (EC) barrier function and suggests that their inhibition by currently available pharmaceutical agents such as imatinib may be EC protective. Here we describe novel and differential effects of imatinib in regulating lung pathophysiology in two clinically relevant experimental models of ALI. Imatinib attenuates endotoxin (LPS)-induced vascular leak and lung inflammation in mice but exacerbates these features in a mouse model of ventilator-induced lung injury (VILI). We next explored these discrepant observations in vitro through investigation of the roles for Abl kinases in cultured lung EC. Imatinib attenuates LPS-induced lung EC permeability, restores VE-cadherin junctions, and reduces inflammation by suppressing VCAM-1 expression and inflammatory cytokine (IL-8 and IL-6) secretion. Conversely, in EC exposed to pathological 18% cyclic stretch (CS) (in vitro model of VILI), imatinib decreases VE-cadherin expression, disrupts cell-cell junctions, and increases IL-8 levels. Downregulation of c-Abl expression with siRNA attenuates LPS-induced VCAM-1 expression, whereas specific reduction of Arg reduces VE-cadherin expression in 18% CS-challenged ECs to mimic the imatinib effects. In summary, imatinib exhibits pulmonary barrier-protective and antiinflammatory effects in LPS-injured mice and lung EC; however, imatinib exacerbates VILI as well as dysfunction in 18% CS-EC. These findings identify the Abl family kinases as important modulators of EC function and potential therapeutic targets in lung injury syndromes.

show abstract

Section: Discussionmentioning

confidence: 91%

mentioning

confidence: 90%

Differential and opposing effects of imatinib on LPS- and ventilator-induced lung injury

Letsiou

Rizzo

Sammani

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

View full text Add to dashboard Cite

show abstract

“…The effect of NO on the microvasculature is complex and not fully understood, with lines of evidence supporting both barrier protective and barrier disruptive behavior (149,726). For instance, cGMP may offer protection from oxidative stress in microvascular ECs (598) and ROS-induced endothelial barrier dysfunction in vitro (427), yet NO-induced elevations in cGMP levels have been implicated in permeability increases following high tidal volume ventilator injury in mice (551). The reasons for these discordant results is unclear; however, emerging evidence suggests that subcompartmentalization of messengers like cGMP, cAMP, kinases and eNOS (541) may allow variable effects on barrier function based on subcellular localization.…”

Section: Transduction Of the Barrier Disruption Signalmentioning

confidence: 99%

Lung Circulation

Suresh

Shimoda

2016

Comprehensive Physiology

111

View full text Add to dashboard Cite

The circulation of the lung is unique both in volume and function. For example, it is the only organ with two circulations: the pulmonary circulation, the main function of which is gas exchange, and the bronchial circulation, a systemic vascular supply that provides oxygenated blood to the walls of the conducting airways, pulmonary arteries and veins. The pulmonary circulation accommodates the entire cardiac output, maintaining high blood flow at low intravascular arterial pressure. As compared with the systemic circulation, pulmonary arteries have thinner walls with much less vascular smooth muscle and a relative lack of basal tone. Factors controlling pulmonary blood flow include vascular structure, gravity, mechanical effects of breathing, and the influence of neural and humoral factors. Pulmonary vascular tone is also altered by hypoxia, which causes pulmonary vasoconstriction. If the hypoxic stimulus persists for a prolonged period, contraction is accompanied by remodeling of the vasculature, resulting in pulmonary hypertension. In addition, genetic and environmental factors can also confer susceptibility to development of pulmonary hypertension. Under normal conditions, the endothelium forms a tight barrier, actively regulating interstitial fluid homeostasis. Infection and inflammation compromise normal barrier homeostasis, resulting in increased permeability and edema formation. This article focuses on reviewing the basics of the lung circulation (pulmonary and bronchial), normal development and transition at birth and vasoregulation. Mechanisms contributing to pathological conditions in the pulmonary circulation, in particular when barrier function is disrupted and during development of pulmonary hypertension, will also be discussed.

show abstract

“…The Abl family kinases, c-Abl (Abl1) and A bl r elated g ene (Arg, Abl2), have recently emerged as key mediators of vascular permeability due to their well characterized roles in the dynamic regulation of the actin cytoskeleton and cell-cell and cell-matrix junctions 5–8 . Several groups have recently reported that the FDA approved Abl kinase inhibitor imatinib attenuates vascular leak induced by thrombin, histamine, vascular endothelial growth factor (VEGF), lipopolysaccharide (LPS), and oxidative stress 9–13 . Although the mechanisms are not fully characterized, it is clear that Abl kinase inhibition has potent and pleiotropic effects on vascular barrier function.…”

Section: Inflammatory Vascular Leak: Overviewmentioning

confidence: 99%

Targeting Abl Kinases to Regulate Vascular Leak During Sepsis and Acute Respiratory Distress Syndrome

Rizzo

Aman

Amerongen

et al. 2015

ATVB

View full text Add to dashboard Cite

The vascular endothelium separates circulating fluid and inflammatory cells from the surrounding tissues. Vascular leak occurs in response to wide-spread inflammatory processes, such as sepsis and Acute Respiratory Distress Syndrome (ARDS), due to the formation of gaps between endothelial cells (EC). Although these disorders are leading causes of mortality in the ICU, no medical therapies exist to restore EC barrier function. Recent evidence highlights a key role for the Abl family of non-receptor tyrosine kinases in regulating vascular barrier integrity. These kinases have well-described roles in cancer progression and neuronal morphogenesis, but their functions in the vasculature have remained enigmatic until recently. The Abl family kinases, c-Abl (Abl1) and Abl related gene (Arg, Abl2), phosphorylate several cytoskeletal effectors that mediate vascular permeability, including myosin light chain kinase, cortactin, vinculin, and β-catenin. They also regulate cell-cell and cell-matrix junction dynamics, and the formation of actin-based cellular protrusions in multiple cell types. Additionally, both c-Abl and Arg are activated by hyperoxia and contribute to oxidant-induced EC injury. These numerous roles of Abl kinases in EC and the current clinical usage of imatinib and other Abl kinase inhibitors have spurred recent interest in repurposing these drugs for the treatment of vascular barrier dysfunction. This review will describe the structure and function of Abl kinases with an emphasis on their roles in mediating vascular barrier integrity. We will also provide a critical evaluation of the potential for exploiting Abl kinase inhibition as a novel therapy for inflammatory vascular leak syndromes.

show abstract

Protein kinase G increases antioxidant function in lung microvascular endothelial cells by inhibiting the c-Abl tyrosine kinase

Cited by 21 publications

References 61 publications

Differential and opposing effects of imatinib on LPS- and ventilator-induced lung injury

Differential and opposing effects of imatinib on LPS- and ventilator-induced lung injury

Lung Circulation

Targeting Abl Kinases to Regulate Vascular Leak During Sepsis and Acute Respiratory Distress Syndrome

Contact Info

Product

Resources

About