Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Scientists Find a Key Protein That Allows Plavix to Conquer Platelets

26.02.2015

The findings could lead to more personalized approaches to controlling platelet activity during heart attacks and other vascular emergencies and diseases.

Researchers at the UNC School of Medicine have found that the blood platelet protein Rasa3 is critical to the success of the common anti-platelet drug Plavix, which breaks up blood clots during heart attacks and other arterial diseases.


Bergmeier lab

Platelets / non-active state


Bergmeier lab

Platelet / activated, sticky to form clot

The discovery, published in the Journal of Clinical Investigation, details how Rasa3 is part of a cellular pathway crucial for platelet activity during clot formation. Understanding the protein’s role could also prove vital in the development of new compounds aimed at altering platelet function.

“We believe these findings could lead to improved strategies for treatment following a heart attack and a better understanding of why people respond differently to anti-platelet drugs, such as aspirin and Plavix,” said Wolfgang Bergmeier, PhD, professor of biochemistry and biophysics, member of the McAllister Heart Institute at UNC, and senior author of the paper.

... more about:
»Medicine »Protein »Rap1 »clot »platelet »proteins »receptor

The research, which was conducted in mice, may also open the door to developing antidotes to Plavix, which was the second-best selling drug in the world prior to its patent expiring in 2012. It is still prescribed under its generic name clopidogrel to millions of people with heart disease, peripheral vascular disease, and cerebrovascular disease.

However, the drug’s anti-platelet effect increases the risk of bleeding in patients and makes emergency surgery too risky because Plavix affects the ability of platelets to prevent blood loss after vascular injury. An antidote would bypass the need to wait until the kidneys eliminate the drug from circulation.

Since the 1970s, scientists knew that clopidogrel had an anti-clotting effect on platelets. In 2001, they found the compound’s target – a cell receptor called P2Y12. As Plavix was developed into a multi-billion-dollar drug, scientists still didn’t know how this receptor communicated with other proteins in the cell pathways important for platelet activation. This also meant they didn’t know why people responded differently to the drug.

Researchers have since learned that the receptor P2Y12 communicates with a small protein called Rap1, which is like a cellular switch. In platelets, this switch is typically off, which keeps platelets in a non-sticky state. In this quiet state, the 2.5 trillion platelets can patrol blood vessels and arteries without sticking to the endothelium – or inside wall – of, say, a coronary artery. If there’s a problem in the endothelium, the Rap1 switch is flipped and platelets morph into super sticky cells that clot fast to keep blood from gushing into tissue.

This is crucial when we have a severe injury or even a cut. But this clotting also happens during a heart attack, when a massive clot is the last thing a person with heart disease needs.

In the arteries that feed blood to the heart, plaque builds over time. But this buildup isn’t typically the cause of heart attacks; they occur when the plaque ruptures and platelets rush in to plug the rupture. This clotting blocks the artery, which blocks oxygen from entering the heart. And that causes the heart attack.

To counteract the effects of the clot, Plavix hits its P2Y12 target to flip the Rap1 switch back to the off position so the platelets return to their quiet, non-sticky state. Aspirin also helps keep platelets from sticking.

Until now, no one knew how hitting the P2Y12 receptor triggered the Rap1 protein to switch off. The experiments conducted by the Bergmeier lab show that the Rasa3 protein is a crucial player in this process.

“Platelets live in unique environment and they need to be very sensitive to changes in that environment,” Bergmeier said. “They are ready to jump into action almost without anything happening. You could say they’re in a preloaded state. But for that to be possible, they need a breaking system that keeps the platelets in the off state so that they don’t do anything until they absolutely have to.”

Rasa3 is a key part of that breaking system, and Plavix makes sure that the break stays on.

Think of a platelet like a circuit with Rap1-GDP representing the off state and Rap1-GTP representing the on state. In between, there are proteins called exchange factors (GEFs), which flip on the platelet’s Rap1 machinery. The proteins needed to switch off Rap1 are called GAPs. (see illustration)

Using deep sequencing techniques, Bergmeier’s team found that Rasa3 was the only highly expressed GAP gene for Rap1 in platelets. He thought that a malfunctioning Rasa3 protein would lead to platelet activation and clearance from circulation.

His team knocked out Rasa3 in mice to show that the offspring had no platelets and could not survive. The researchers then used mice from The Jackson Laboratory to study platelets in mice with a Rasa3 mutation. These mice had 3 to 5 percent of the typical platelet count. Bergmeier’s team found that the rest of the platelets were being activated and cleared from circulation.

When the researchers disabled the major GEF proteins, the platelet counts rose to normal amounts in the mice. This showed that a tightly controlled balance between GEF and GAP proteins, especially Rasa3, is vital for platelet activity.

At the sites of vascular injury there’s a shift in this balance inside a platelet that makes the cells very sticky. Plavix ensures that Rasa3 cannot be turned off in platelets; the drug irreversibly limits the cell’s ability to stick. It keeps the cell’s breaking system perpetually on.

“These experiments show that this Rap1 GEF-GAP pathway is crucial for platelets to jump into action to plug a hole in the endothelium,” Bergmeier said. “And now we know that Rasa3 is a critical negative regulator, a break, on the process.”

Bergmeier added, “We have good reason to believe that the Rap1 switch, controlled by the same GEF and GAP proteins, also regulates the active state of human platelets. We expect this research will provide critical information for improving anti-platelet therapies, possibly including approaches that eliminate some of the patient-to-patient variability and the increased bleeding risk associated with current anti-platelet drugs.”

Co-first authors of the study are David Paul, PhD, and Lucia Stefanini, PhD, both postdoctoral fellows in the Bergmeier lab when this research was conducted. Stefanini is now member of the Institute for Cardiovascular and Metabolic Research at the University of Reading in the United Kingdom. The co-corresponding author, along with Bergmeier, is Luanne Peters, PhD, professor at The Jackson Laboratory.

Other UNC authors include Kathleen Caron, PhD, professor and chair of the department of cell biology and physiology; Nigel Mackman, PhD, the John C. Parker Professor of Medicine and director of the McAllister Heart Institute; Matthew Parrott, PhD, assistant professor of radiology and member of the UNC Biomedical Research Imaging Center; Todd Getz, PhD, former UNC graduate student and current ORISE research fellow the U.S. Army Institute of Surgical Research; Yacine Boulaftali, PhD, and Caterina Casari, PhD, both postdoctoral fellows in the Bergmeier lab; and graduate student Dan Kechele.

This research was supported through grants from the National Institutes of Health, The American Heart Association, the European Hematology Association, and the International Society of Thrombosis and Hemostasis.

Contact Information
Mark Derewicz
Science Communications Manager
mark.derewicz@unch.unc.edu

Mark Derewicz | newswise

Further reports about: Medicine Protein Rap1 clot platelet proteins receptor

More articles from Life Sciences:

nachricht The secret sulfate code that lets the bad Tau in
16.07.2018 | American Society for Biochemistry and Molecular Biology

nachricht Colorectal cancer risk factors decrypted
13.07.2018 | Max-Planck-Institut für Stoffwechselforschung

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: First evidence on the source of extragalactic particles

For the first time ever, scientists have determined the cosmic origin of highest-energy neutrinos. A research group led by IceCube scientist Elisa Resconi, spokesperson of the Collaborative Research Center SFB1258 at the Technical University of Munich (TUM), provides an important piece of evidence that the particles detected by the IceCube neutrino telescope at the South Pole originate from a galaxy four billion light-years away from Earth.

To rule out other origins with certainty, the team led by neutrino physicist Elisa Resconi from the Technical University of Munich and multi-wavelength...

Im Focus: Magnetic vortices: Two independent magnetic skyrmion phases discovered in a single material

For the first time a team of researchers have discovered two different phases of magnetic skyrmions in a single material. Physicists of the Technical Universities of Munich and Dresden and the University of Cologne can now better study and understand the properties of these magnetic structures, which are important for both basic research and applications.

Whirlpools are an everyday experience in a bath tub: When the water is drained a circular vortex is formed. Typically, such whirls are rather stable. Similar...

Im Focus: Breaking the bond: To take part or not?

Physicists working with Roland Wester at the University of Innsbruck have investigated if and how chemical reactions can be influenced by targeted vibrational excitation of the reactants. They were able to demonstrate that excitation with a laser beam does not affect the efficiency of a chemical exchange reaction and that the excited molecular group acts only as a spectator in the reaction.

A frequently used reaction in organic chemistry is nucleophilic substitution. It plays, for example, an important role in in the synthesis of new chemical...

Im Focus: New 2D Spectroscopy Methods

Optical spectroscopy allows investigating the energy structure and dynamic properties of complex quantum systems. Researchers from the University of Würzburg present two new approaches of coherent two-dimensional spectroscopy.

"Put an excitation into the system and observe how it evolves." According to physicist Professor Tobias Brixner, this is the credo of optical spectroscopy....

Im Focus: Chemical reactions in the light of ultrashort X-ray pulses from free-electron lasers

Ultra-short, high-intensity X-ray flashes open the door to the foundations of chemical reactions. Free-electron lasers generate these kinds of pulses, but there is a catch: the pulses vary in duration and energy. An international research team has now presented a solution: Using a ring of 16 detectors and a circularly polarized laser beam, they can determine both factors with attosecond accuracy.

Free-electron lasers (FELs) generate extremely short and intense X-ray flashes. Researchers can use these flashes to resolve structures with diameters on the...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Leading experts in Diabetes, Metabolism and Biomedical Engineering discuss Precision Medicine

13.07.2018 | Event News

Conference on Laser Polishing – LaP: Fine Tuning for Surfaces

12.07.2018 | Event News

11th European Wood-based Panel Symposium 2018: Meeting point for the wood-based materials industry

03.07.2018 | Event News

 
Latest News

Leading experts in Diabetes, Metabolism and Biomedical Engineering discuss Precision Medicine

13.07.2018 | Event News

Research finds new molecular structures in boron-based nanoclusters

13.07.2018 | Materials Sciences

Algae Have Land Genes

13.07.2018 | Life Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>