Knocking Out Smoking and Pulmonary Hypertension with a K.

Although many patients with chronic obstructive pulmonary disease (COPD) develop mild pulmonary arterial hypertension (PAH), believed to result from hypoxia-induced pulmonary vasoconstriction, a small but significant fraction of patients with COPD develop more severe PAH, often without clinical evidence of hypoxemia or out of proportion to their degree of emphysema (1, 2). The mechanism for the development of pulmonary hypertension in these patients is not entirely clear, but pathologically, the pulmonary arterioles of these patients demonstrate endothelial cell dysfunction (3), smooth muscle cell hyperplasia, and arterial intimal fibrosis (4), features commonly observed in other forms of primary or group I PAH. As a consequence, these patients suffer significant morbidity and mortality, often independent of the severity of their obstructive airway disease (5). Why some patients with COPD develop significant PAH and the mechanisms that drive this process are not completely understood.

The harmful effects of cigarette smoke are well known to not only directly affect cells of the respiratory epithelium but also other cell types in the lung, including mesenchymal cells and vascular endothelial cells (6). Indeed, the ability of toxins from cigarette smoking to traverse the epithelial barrier and effect pulmonary and systemic vasculature is an oft-cited mechanism for how smoking contributes to cardiovascular disease, stroke, and other systemic diseases (7). Not surprisingly, tobacco smoking is also a risk factor for PAH (8).

Dynamic vasoconstriction and vasodilation are mediated by the contraction and relaxation of smooth muscle and mesenchymal cells of the vasculature, and like most muscle cells, they are mediated by the opening and closing of various ion channels. From the initial discovery of action potentials described by Hodgkin and Huxley in 1952, ion channel behavior is one of the oldest and most fundamental processes that has been studied in cell and molecular physiology. Patch clamp recordings, invented by Neher and Sakmann, provided a technique to study electrophysiology at the level of individual ion channels and cells. Today, we know the human genome codes for more than 300 different ion channels, whose function are not only limited to electrochemical homeostasis or neuronal communication but also to diverse functions including cell proliferation, differentiation, mitochondrial function, cellular metabolism, DNA repair, and cell–cell communication. Beyond muscle contraction, ion channels play a role in organ development, repair and regeneration, aging, and cellular senescence.

Potassium (K+) channels themselves have been in eukaryotic, bacterial, and archaeal existence since before the evolution of neuronal signaling (9). They are found in nearly all organisms and cell types (10). In humans, they are often classified by their structure (for example, inward-rectifying K+ channels have two transmembrane domains, whereas others have six) and gating mechanisms, where they may either remain constitutively open to help maintain resting membrane potential or open only in response to changes in voltage (often designated Kv) or calcium. Abnormalities in K+ channels have been implicated in PAH; indeed, PAH has been associated with genetic defects in ABCC8 and KCNK3 (11, 12). KCNK3, which is also called TASK1, belongs to a family of tandem-pore domain K+ channels that maintain resting membrane potential and can be inhibited by local anesthetics, including lidocaine and bupivacaine. Endothelin-1 and serotonin, which are elevated in PAH, also inhibit KCNK3 function (13). Loss of KCNK3 function by these mediators contributes to PAH by promoting vasoconstriction and pulmonary artery smooth muscle proliferation (14). Dysfunction of voltage-gated K+ channels, including Kv1.5 (KCNA5), has also been implicated in PAH. PAH is associated with single-nucleotide polymorphisms in KCNA5 (15), and loss of Kv1.5 function in pulmonary artery smooth muscle cells contributes to increased cytosolic Ca2+ concentration and smooth muscle contraction.

In this issue of the Journal, Sevilla-Montero and colleagues (pp. 1290–1305) examine the role of Kv7.4 (KCNQ4) in cigarette-smoking–induced pulmonary vascular remodeling (16). Members of the Kv7 family are also highly expressed in vascular smooth muscle, and Kv7.4 has been implicated in systemic hypertension (17). Sevilla-Montero and colleagues show that cigarette smoking contributes to pulmonary arterial remodeling via induction of arterial smooth muscle and adventitial fibroblast senescence. They then show that cigarette smoking contributes to loss of Kv7.4 expression, and this leads to impaired vasodilation (Figure 1). They also interestingly observed impaired vasoactive constriction as well in response to serotonin. Cigarette-induced impairment in vasoactivity and loss of Kv7.4 were later confirmed in animal models and finally in human tissue of patients with COPD.

Figure 1.

Schematic representation of the effects of cigarette smoking on Kv7.4 expression and vascular remodeling. SASP = senescence-associated secretory phenotype.

Although these studies provide a comprehensive and elegant analysis of how loss of Kv7.4 might contribute to cigarette-induced pulmonary vascular remodeling and PAH, many questions remain. Voltage-gated K+ channels like Kv7.4 allow cells to repolarize and are thus critical for smooth muscle relaxation; loss of Kv7.4 would thus be expected to contribute to PAH through impaired vasodilation. However, cigarette smoke was also shown by the authors to impair vascular responsiveness to vasoconstricting agents as well, and whether this may be due to loss of Kv7.4 is unclear. It is increasingly recognized that PAH is characterized by not just impairment in vascular relaxation but also in defects of overall vascular responsiveness to both vasodilating and vasoconstricting agents. How might loss of Kv7.4 cause impairment in vasoconstriction? Could cigarette smoking induce gain (or loss) of function of other ion channels that results in impaired vascular responsiveness?

In the study by Sevilla-Montero and colleagues, cigarette smoke exposure was also observed to contribute to arterial smooth muscle and fibroblast senescence (16), but how it does so and whether it is dependent on loss of Kv7.4 is not known. The effect of K+ channel opening is best thought to result in cellular repolarization, and K+ ions themselves are not often considered second messengers in signaling. However, the importance of K+ channels in diverse cellular processes suggests that their actions likely induce a variety of downstream signaling effects, only some of which have been explored. K+ channels, including Kv7.4, are known to locate not just on plasma membrane but also in organelles including mitochondria (18), affecting cellular metabolism, aging, and survival. Different classes of K+ channels, many of which are expressed simultaneously in a given cell, also offer different gating thresholds and electrochemical properties; how they integrate in a systems-based fashion to regulate diverse processes such as cell proliferation, differentiation, senescence, and metabolism remain a mystery.

The function of K+ channels has historically been focused on neurons, cardiac muscle, and systemic vasculature, but accumulating evidence has shown alterations in K+ channel biology to be important in asthma, COPD, and pulmonary fibrosis (19, 20). Specificity of different K+ channels and their expression on cell surfaces lend themselves to easy therapeutic targeting by agonists and antagonists. The work by Sevilla-Montero and colleagues leads to a long line of accumulating evidence of the importance of K+ channels in not just PAH but also a variety of lung diseases and offers unique opportunities for targeting specific K+ channels as a novel line of therapeutics.