Hitting the Platelet Off ‘Switch’
In the early 1900’s the leading cause of death in the United States was due to infectious diseases. The average expected lifespan was approximately 50 years, and therefore chronic diseases were not as impactful on the general population. As lifespan increased throughout the century, the critical role of cardiovascular disease and chronic hypertension was revealed as a silent burden plaguing the country and the world. Currently, CVD is a leading global cause of death, particularly in developing nations with inadequate access to medical care and treatment. Some contributors to CVD are familial hypercholesterolemia, hypertension, diabetes, smoking, and a high cholesterol diet. Due to its prevalence and complex etiology, it is critical to identify new treatment options that can prevent and treat patients at risk for major cardiovascular events.
Cardiovascular disease begins with the formation of fatty streaks along the arteries, which signify the accumulation of cholesterol beneath the vessel wall. The vessel wall is composed of a monolayer of tightly packed cells known as endothelial cells (ECs). A major role of ECs is to maintain the structural integrity of the vessel wall to prevent hemorrhaging, while simultaneously creating a non-adhesive environment so blood cells can easily pass through. As CVD progresses, the fatty streak begins to irreversibly disrupt the endothelial cell barrier as well as induce endothelial cells to display receptors that make them “sticky.” Subsequently, platelets, white blood cells, and erythrocytes begin adhering to these sites, contributing to a highly inflammatory environment. Over time, a series of remodeling events progress resulting in fibrous lesion formation known as the atherosclerotic plaque. These plaques tend to be unstable and their rupture can be triggered by a number of stressful events. Immediately after the plaque rupture, platelets adhere to the injured site and accumulate into a relatively large thrombus. In severe cases, these thrombi can occlude the vasculature (ischemia) or detach and possibly occlude the vasculature of the heart (myocardial infarction/MI) or the brain (stroke). Therefore, there is great interest in developing anti-platelet drugs as potential therapies against MI and stroke.
Jimmy Schiemer, a PhD student in the Cellular & Molecular Physiology PhD program has been conducting his thesis work in this area. His adviser, Athar Chishti has a long-term interest in investigating the molecular mechanisms of thrombus formation. Platelets must bind to soluble ‘bridging’ molecules in the blood that can link two or more platelets together. This process is facilitated by a series of signaling events within platelets that culminate in the activation of receptors on the platelet surface. These signaling events are accomplished through the mobilization of calcium, which activates a family of proteins known as G proteins. Activation of G proteins in platelets leads to a multitude of signaling processes that are indispensable for platelet functionality. We and our collaborators have recently developed a novel small peptide based therapeutic approach against platelet Gα13 that can dramatically diminish thrombus formation in vivo. The treatment is based on a highly conserved Switch Region 2 sequence of Gα13 that plays a crucial role in platelet activation. These findings may lead to new anti-thrombotic drugs as potential prophylactic treatment for patients at risk for major cardiovascular events.
Schiemer J, Bohm A, Lin L, Merrill-Skoloff G, Flaumenhaft R, Huang JS, Le Breton GC, Chishti AH. 2016. Gα13 switch region 2 relieves talin autoinhibition to activate IαIbβ3 integrin. J Biol Chem. 291(52): 26598-26612.
Srinivasan S, Schiemer J, Zhang X, Chishti AH, Le Breton GC. 2015. Gα13 switch region 2 binds to the talin head domain and activates αIIbβ3 integrin in human platelets. J Biol Chem. 290(41): 25129-25139.