The role of PKDs in atherosclerosis & coronary heart disease

Cardiovascular disease (CVD) is the number one cause of human morbidity and mortality in the developed world. Overwhelming evidence has pointed to a direct causal role of tobacco use in CVD progression. Many reports convincingly demonstrate that CVD is the greatest cause of smoking-related premature death. Atherosclerosis can be considered to be a vascular disorder resulting from a response to injury initiated by circulating factors, including nicotine, and leads to CVD. It has been shown that cigarette smoking promotes endothelial dysfunction and accelerates atherosclerosis. Continuous smoking impairs flow-mediated dilatation (FMD) of the brachial artery in a dose-dependent manner in healthy young adults. Altered FMD is a well-defined early marker for endothelial dysfunction. Critically, reduction of endothelium-dependent dilatation caused by smoking is reversible.

Vascular endothelial cells (ECs) line the entire circulatory system and play an essential role in health and disease. The endothelium not only provides a physical barrier to control vascular permeability, it also releases a large number of vasoactive substances to regulate vascular tone and vessel wall remodeling. Endothelial dysfunction, the initiating step of atherosclerosis, causes enhanced recruitment and retention of pro-inflammatory macrophages and T lymphocytes and diminishes production of Nitric oxide (NO). Protein kinase D (PKD) has recently emerged as a family of serine/threonine kinases with important cardiovascular actions. Several studies suggest a critical role for PKD in vascular biology and in cardiac ischemia. Our preliminary studies showed that PKD activity controls endothelial NO synthesis. However, there is a lack of in vivo evidence for the role of PKD in ECs, as well as a lack of insight into mechanisms by which PKD affects vascular biology. Our proposed studies are to test our hypothesis that endothelial PKDs play a protective role in the setting of cardiac ischemia, and in the progression of atherosclerosis, through the regulation of NO production. Results obtained from our proposed study will increase our knowledge of the specific roles of PKD in ECs during myocardial ischemia and atherosclerosis. An in depth understanding of pathways regulated by PKD in ECs is likely to yield new therapeutic targets for smoking-related vascular disorders.