The role for Connexins in Cardiovascular Diseases and Treatments

Diseases of the blood vessels and heart have the highest mortality rates in the world. In advanced disease, critical blood vessels can become blocked by a build-up of cells and lipids within the walls of the blood vessel. This can severely limit blood flow to affected organs such as the heart and is a major cause of high blood pressure, heart attacks and stroke. Treatments include surgery to restore blood flow by re-widening of the blood vessels by balloon catheter and permanent placement of a metal supports called ‘stents’ or by blood vessel bypass. These surgeries can alleviate symptoms but cause blood vessel damage that promotes surrounding cells to divide and blood vessel re-narrowing in a high number of patients. We have recently identified that proteins called connexins, found in all blood vessel cells, are directly linked to the regulation of cell division. My work focuses on identifying the impact of specific connexin proteins in blood vessel disease, defining how they interact with other proteins to promote cells to divide and ways in which we can disrupt the protein in disease. This could potentially lead to novel therapeutic targets for treatment of blood vessel diseases.

Atherosclerosis is the major underlying condition in cardiovascular disease with complications including heart attack, stroke and hypertension that cause 1 in 3 deaths worldwide. The annual direct and indirect costs across Europe for cardiovascular diseases exceed €500bn (World Health Organization) far outweighing those of cancer (€146bn) and HIV (€22.4bn). Deaths due to cardiovascular disease are considered premature and preventable through combinations of lifestyle and therapeutic interventions. Therefore, cardiovascular diseases and their treatments are a major economic burden in the EU and on the health of the population in general.

In advanced disease, the most common treatments are either coronary angioplasty and stent placement or coronary artery bypass graft surgeries (CABG). Both of these treatments come with the side effect of triggering neointimal formation through smooth muscle cell division and migration within the walls of the blood vessel. Neointimal formation is a significant problem and requires further revascularization surgery in around 10-50% of patients within 10 years of the initial surgery. Understanding the causes of neointimal formation would allow for more specific targets of its development, could improve long-term patient outcomes post-surgery and could reduce costs additional surgeries.

Ideally, the capacity to specifically target single proteins which regulate the pathways involved in smooth muscle cell proliferation and migration may lead to more specific treatments for neointimal formation with reduced side effects. Recently we identified a novel interaction between connexin 43 (Cx43) and the cell cycle control protein cyclin E (Johnstone et al Circ. Res. 2012). This finding is a major breakthrough in understanding how the connexins can directly regulate cellular proliferation which has been the focus of over 50 years of study. Moreover, we have been the first to identify that post-translational events i.e. MAPK phosphorylation of Cx43, as critical in the regulation of this interaction and smooth muscle cell proliferation in response. This leads to the exciting possibility that specific protein regions could be targeted to disrupt pathological smooth muscle responses while preserving physiological protein function within the cell.

The objectives of my current studies are to provide mechanistic insight and initial drug discovery of the molecular targets of cellular proliferation, migration and apoptosis during vascular disease. The longer-term goals are to understand the underlying causes, to identify early biomarkers and to develop treatments in human vascular disease that could reduce neointimal formation, minimize surgical side effects and increase long-term patient survival. 

Publications

1. Johnstone SR, Kronke B, Straub AC, Best AK, Dunn CA, Mitchell LA, Peskova Y, Nakomoto RK, Koval M, Lampe PD, Columbus L and Isakson BE. MAPK phosphorylation of connexin 43 promotes binding of cyclin E and smooth muscle cell proliferation. Circ Res. 2012;111:201-211
2. Johnstone SR, Billaud M, Lohman AW, Taddeo EP and Isakson BE. Post-translational modifications in connexins and pannexins. J Memb Biol. 2012;245:319-332
3. Johnstone SR,  Best AK, Wright CS, Isakson BE, Errington RJ and Martin PE. Increased connexin 43 expression regulates cell cycle progression independent of channel function. J Cell Biochem. 2012;110:772-82
4. Straub AC, Johnstone SR, Heberlein KR, Rizzo MJ, Best AK, Boitano S and Isakson BE. Site-specific connexin phosphorylation is associated with reduced heterocellular communication between smooth muscle and endothelium. J Vasc Res. 2010;47:277-286
5. Johnstone SR, Isakson BE and Locke D. Biological and biophysical properties of vascular connexin channels. Int Rev Cell Mol Biol. 2009;278:69-118
6. Johnstone SR, Ross J, Rizzo MJ, Straub AC, Lampe PD, Leitinger N and Isakson BE. Oxidized phospholipid species promote in vivo differential Cx43 phosphorylation and vascular Smooth muscle cell proliferation. Am J Pathol. 2009;175:916-24