Hypoxic Regulation of the Large-Conductance, Calcium and Voltage-Activated Potassium Channel, BK

Abstract

Hypoxia is a condition characterized by a reduction of cellular oxygen levels derived from alterations in oxygen balance. Hypoxic events trigger changes in cell-signaling cascades, oxidative stress, activation of pro-inflammatory molecules, and growth factors, influencing the activity of various ion channel families and leading to diverse cardiovascular diseases such as myocardial infarction, ischemic stroke, and hypertension. The large-conductance, calcium and voltage-activated potassium channel (BK) has a central role in the mechanism of oxygen (O2) sensing and its activity has been related to the hypoxic response. BK channels are ubiquitously expressed, and they are composed by the pore-forming α subunit and the regulatory subunits β (β1–β4), γ (γ1–γ4), and LINGO1. The modification of biophysical properties of BK channels by β subunits underly a myriad of physiological function of these proteins. Hypoxia induces tissue-specific modifications of BK channel α and β subunits expression. Moreover, hypoxia modifies channel activation kinetics and voltage and/or calcium dependence. The reported effects on the BK channel properties are associated with events such as the increase of reactive oxygen species (ROS) production, increases of intracellular Calcium ([Ca2+]i), the regulation by Hypoxia-inducible factor 1α (HIF-1α), and the interaction with hemeproteins. Bronchial asthma, chronic obstructive pulmonary diseases (COPD), and obstructive sleep apnea (OSA), among others, can provoke hypoxia. Untreated OSA patients showed a decrease in BK-β1 subunit mRNA levels and high arterial tension. Treatment with continuous positive airway pressure (CPAP) upregulated β1 subunit mRNA level, decreased arterial pressures, and improved endothelial function coupled with a reduction in morbidity and mortality associated with OSA. These reports suggest that the BK channel has a role in the response involved in hypoxia-associated hypertension derived from OSA. Thus, this review aims to describe the mechanisms involved in the BK channel activation after a hypoxic stimulus and their relationship with disorders like OSA. A deep understanding of the molecular mechanism involved in hypoxic response may help in the therapeutic approaches to treat the pathological processes associated with diseases involving cellular hypoxia.

Chronic Kidney Disease Induces Proarrhythmic Remodeling

“…30–43 Of these 13 hypoxia-related genes, 10 shared a connection to the well-known HIF (hypoxia-inducible factor) pathway (Apln, Egln3, Eif4ebp1, Fmo2, Gnmt, Lrrc55, Mycn, Nqo1, Nt5e, and P4ha1). 30–33,35,36,38–40,42 A subset of these HIF-related transcripts are illustrated in Figure 5B.…”

“…[30][31][32][33][34][35][36][37][38][39][40][41][42][43] Of these 13 hypoxiarelated genes, 10 shared a connection to the well-known HIF (hypoxia-inducible factor) pathway (Apln, Egln3, Eif4ebp1, Fmo2, Gnmt, Lrrc55, Mycn, Nqo1, Nt5e, and P4ha1). [30][31][32][33]35,36,[38][39][40]42 A subset of these HIF-related transcripts are illustrated in Figure 5B. RBM3 and CIRP have known roles in physiologic stress response.…”

“…Interestingly, we also observed that 13 of the 25 most significant DEGs in our sample were previously implicated in cellular response to hypoxia (Apln, Egln3, Eif4ebp1, Fmo2, Gnmt, Lrrc55, Mr1, Mycn, Nqo1, Nt5e, P4ha1, Prps1, and Trnp1; Figure 5A). [30][31][32][33][34][35][36][37][38][39][40][41][42][43] Of these 13 hypoxiarelated genes, 10 shared a connection to the well-known HIF (hypoxia-inducible factor) pathway (Apln, Egln3, Eif4ebp1, Fmo2, Gnmt, Lrrc55, Mycn, Nqo1, Nt5e, and P4ha1). [30][31][32][33]35,36,[38][39][40]42 A subset of these HIF-related transcripts are illustrated in Figure 5B.…”

“…This list of 13 genes includes myofibrillogenesis regulator-1 (Mr-1), which has previously been shown to regulate apoptosis in the setting of ischemia-reperfusion injury of cardiac myocytes, 41 5 potential upstream regulators of the HIF pathway (Egln3, Gnmt, Mycn, Nqo1, and P4ha1), and 7 downstream targets of HIF (Apln, Egln3, Eif4ebp1, Fmo2, Lrrc55, P4ha1, and Nt5e). [30][31][32][33]35,36,[38][39][40]42 Although no studies have demonstrated a direct link between the HIF pathway and cardiac arrhythmias, several lines of experiments have revealed that the HIF pathway regulates EPO production and iron transport in the setting of CKD-associated hypoxia, 60 and HIF prolyl hydroxylase enzyme inhibitors, which have been shown to stimulate EPO production in patients with CKD by stabilizing the HIF complex, are currently under study in phase 2 and phase 3 clinical trials for therapeutic management of anemia in CKD. 61 As with the increased expression of CIRP and RBM3, the confluence of hypoxia-related genes at the top of our differentially expressed gene list is consistent with the notion that tissue hypoxia may play a mechanistic role driving the pathologic transcriptional remodeling observed in this model of CKD.…”

Hypoxic Stress-Dependent Regulation of Na,K-ATPase in Ischemic Heart Disease

“…Our group recently showed that HIF-2α is involved in preventing internalization and degradation of surface expression of epithelial Na channels (ENaC) in primary alveolar epithelial cells exposed to in vitro hypoxia, and it improved the amiloride-sensitive alveolar fluid reabsorption, which was decreased in in vivo hypoxia [89]. Ochoa et al recently reviewed the regulation of the calcium and voltage-activated potassium channel (BK) by hypoxia, HIF-1α and its relation with CVD [90]. Most of these studies have been performed in vitro; thus, whether similar regulations by HIFs also occur in vivo still needs to be identified.…”