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Blood-vessel-on-a-chip provides insight into new anti-inflammatory drug candidate

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Activated protein C is a naturally occurring anti-coagulant protein with anti-inflammatory and other protective effects that has been used medically to treat severe blood infections and wounds; however, its use is limited because its inhibition of thrombin also impacts the blood’s ability to clot, increasing bleeding risk.

Now, a collaborative team of researchers from the Division of Hemostasis and Thrombosis at Beth Israel Deaconess Medical Center and the Wyss Institute at Harvard University have discovered that synthetic APC-mimicking small molecules called “Parmodulins” provide anti-inflammatory and anti-thrombotic protection to endothelial cells on par with APC’s without interfering with blood clotting, making them attractive new drug candidates.

“We essentially performed a mini pre-clinical trial of parmodulins’ effect on the endothelium, and not only determined the pathway through which parmodulins function, but also demonstrated that they help protect endothelial cells from inflammatory damage,” says former Wyss postdoc Abhishek Jain, Ph.D., who is now an Assistant Professor and director of the the Bioinspired Translational Microsystems lab at Texas A&M University.

The target protein on which both APC and parmodulins act is the transmembrane protein protease-activated receptor 1, which is present on both endothelial cells that line blood vessels and platelets that circulate through the blood and promote clotting, making mechanistic analysis difficult.

“We were intrigued by the notion that parmodulin 2 inhibited LPS- and TNF-mediated prothrombotic effects on the endothelial surface without impairing blood clotting” says De Ceunynck.

These results indicated that parmodulin exposure blocks the thrombotic response of endothelium to inflammatory stimuli without affecting blood coagulation in humans – a significant improvement over APC. A series of tests in vitro performed by co-first author Christian Peters, Ph.D. at BIDMC, confirmed that parmodulin 2’s activation of PAR1 also induces cytoprotective responses in endothelial cells by inhibiting apoptosis induced by thrombin, TNF-α, and the apoptotic alkaloid staurosporine through a signaling pathway that begins with parmodulin 2’s binding to a specific site on the cytoplasmic side of PAR1.

In vivo studies in mice showed that parmodulin 2 reduces the binding of white blood cells to blood vessels and impairs platelet and fibrin accumulation at injury sites during the inflammatory response, confirming the anti-thrombotic and anti-coagulant activity of parmodulin 2 observed in vitro.

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Article originally posted at medicalxpress.com

Post Author: Bernard Marr

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