Potassium channel dysfunction plays a role in the pathogenesis of a number of vascular diseases including pulmonary and systemic hypertension, diabetes, and complications of atherosclerosis. Two types of K+ channels that are known to be prevalent and contribute significantly to the repolarization of vascular smooth muscle cell (SMC) membranes are the high-conductance Ca2+- and voltage-activated K+ (BKCa) channels, and the voltage-gated K+ (KV) channels. Alterations in either BKCa or KV channel function can have dramatic effects on vascular tone. To date, hereditary and congenital mutations in genes encoding K+ channels, abnormalities in transcription, posttranslational modifications, and altered responses to intracellular second messengers have been described as potential mechanisms for several cardiovascular diseases. Comprehensive approaches including genetic, biochemical, molecular biological, and electrophysiological analyses are necessary to identify the levels at which K+ channel expression patterns or function are disrupted. Additionally, reproducing clinical pathologies in animal, organ, and virtual models has been important in studying the discrete mechanisms by which the structure and function of these channels are altered in pathophysiological conditions. This article will describe approaches that are currently used to identify abnormalities in BKCa and KV channels that may exist in diseases involving vascular dysfunction.
Activation of endothelial cells by proinflammatory stimuli results in increased migration of leukocytes across the endothelium, which contributes to the progression of atherosclerosis. Thus, control of the inflammatory status of endothelial cells, which is achieved by a balance of pro- and antiinflammatory signals, is crucial to limiting the disease. The mitogen-activated protein kinases (MAPKs) are a family of central signaling molecules that respond to numerous stimuli by phosphorylating a variety of substrates including transcription factors, enzymes, and other kinases. While the extracellular signal-related kinases (ERK1/2) and big MAPK-1 (BMK1) are primarily involved in growth and cytoprotective functions, Jun amino-terminal kinases (JNK) and p38 proteins play an important role in inflammatory and stress responses. Because they have contradictory roles, the relative activation of these proteins is important to the inflammatory status of the cell. Additionally, there is known to be a crosstalk between MAPK cascades whereby the activity of one MAPK can be influenced by another. Thus, these proteins collectively integrate the pro- and antiinflammatory stimuli acting on the cell to produce the appropriate downstream effects. Here we review the roles of the MAPKs and the implications of MAPK crosstalk on endothelial activation.
(1) Chemokines play a central role in the pathogenesis of atherosclerosis, contributing to leukocyte recruitment, angiogenesis and also proliferation and migration of smooth muscle cells into atherosclerotic plaques. (2) Leukocytes and endothelial cells are an important source of chemokines, and many of the risk factors associated with atherosclerosis increase chemokine expression. There is now a body of evidence to suggest that interactions between cells such as leukocytes and endothelial cells amplify chemokine release, and this may contribute to sustained chemokine generation in inflammatory conditions. (3) This article summarises, briefly, what is currently known about chemokines release. A number of important pharmacological strategies used in the treatment of atherosclerosis inhibit chemokine release and the extent to which this may contribute to their therapeutic effect will be discussed. Understanding the mechanisms controlling chemokine expression is essential for the design of specific therapeutic interventions in atherosclerosis.
Altered function of K+ channels associated with hypertension has been inferred from the effects of K+ channel blockers on contraction of arterial smooth muscle cells (SMCs) and from K+ efflux measurements. Of the classes of K+ channels known to exist in the smooth muscle, the contribution of voltage-gated (KV) and high-conductance, Ca2+ gated K+ (BKCa) channels to the regulation of arterial SMC contractile function has been the most studied in hypertension. The effects of selective and nonselective K+ channel blockers on tonic contraction suggest that these two K+ channel gene families contribute differently to total K+ conductance in arterial SMCs from normal and hypertensive subjects. Direct measurements of K+ channel properties by electrophysiological methods generally support this conclusion. Studies have demonstrated larger BKCa currents in SMCs from several arteries of hypertensive rats, which have been reported to result from a greater Ca2+ sensitivity of BKCa channels and/or from greater protein expression. Some, but not all, studies have shown decreased KV currents in arterial SMCs from hypertensive animals measured under Ca(2+)-replete conditions. However, when external Ca2+ is removed or when Ca2+ influx is inhibited, KV currents are larger in SMCs exposed to chronic hypertension. Gene expression studies of Shaker KV1 transcripts have shown that of the dominant species present in arterial SMCs, KV1.2 expression is higher, whereas KV1.5 is the same in SMCs from hypertensive compared to normal animals. This finding is consistent with the larger KV currents in vascular SMCs from hypertensive animals under low Ca2+ conditions and suggests that Ca2+ influx and/or intracellular Ca2+ per se exerts a greater inhibitory effect on KV currents in the myocytes from these animals. The pathways by which these K+ channel differences are produced during hypertension remain to be elucidated, as does the potential for these channel proteins to be targeted by novel antihypertensive therapies.
