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 Scientists unlock ability to generate new sensory hair cells
22.02.2017 | Brigham and Women's Hospital

nachricht New insights into the information processing of motor neurons
22.02.2017 | Max Planck Florida Institute for Neuroscience

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Breakthrough with a chain of gold atoms

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

Im Focus: DNA repair: a new letter in the cell alphabet

Results reveal how discoveries may be hidden in scientific “blind spots”

Cells need to repair damaged DNA in our genes to prevent the development of cancer and other diseases. Our cells therefore activate and send “repair-proteins”...

Im Focus: Dresdner scientists print tomorrow’s world

The Fraunhofer IWS Dresden and Technische Universität Dresden inaugurated their jointly operated Center for Additive Manufacturing Dresden (AMCD) with a festive ceremony on February 7, 2017. Scientists from various disciplines perform research on materials, additive manufacturing processes and innovative technologies, which build up components in a layer by layer process. This technology opens up new horizons for component design and combinations of functions. For example during fabrication, electrical conductors and sensors are already able to be additively manufactured into components. They provide information about stress conditions of a product during operation.

The 3D-printing technology, or additive manufacturing as it is often called, has long made the step out of scientific research laboratories into industrial...

Im Focus: Mimicking nature's cellular architectures via 3-D printing

Research offers new level of control over the structure of 3-D printed materials

Nature does amazing things with limited design materials. Grass, for example, can support its own weight, resist strong wind loads, and recover after being...

Im Focus: Three Magnetic States for Each Hole

Nanometer-scale magnetic perforated grids could create new possibilities for computing. Together with international colleagues, scientists from the Helmholtz Zentrum Dresden-Rossendorf (HZDR) have shown how a cobalt grid can be reliably programmed at room temperature. In addition they discovered that for every hole ("antidot") three magnetic states can be configured. The results have been published in the journal "Scientific Reports".

Physicist Dr. Rantej Bali from the HZDR, together with scientists from Singapore and Australia, designed a special grid structure in a thin layer of cobalt in...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Booth and panel discussion – The Lindau Nobel Laureate Meetings at the AAAS 2017 Annual Meeting

13.02.2017 | Event News

Complex Loading versus Hidden Reserves

10.02.2017 | Event News

International Conference on Crystal Growth in Freiburg

09.02.2017 | Event News

 
Latest News

Positrons as a new tool for lithium ion battery research: Holes in the electrode

22.02.2017 | Power and Electrical Engineering

New insights into the information processing of motor neurons

22.02.2017 | Life Sciences

Healthy Hiking in Smart Socks

22.02.2017 | Innovative Products

VideoLinks
B2B-VideoLinks
More VideoLinks >>>