Endothelial Small- and Intermediate-Conductance K Channels and Endothelium-Dependent Hyperpolarization as Drug Targets in Cardiovascular Disease

Inhibition of Intermediate-Conductance Calcium-Activated K Channel (KCa3.1) and Fibroblast Mitogenesis by α-Linolenic Acid and Alterations of Channel Expression in the Lysosomal Storage Disorders, Fabry Disease, and Niemann Pick C

“…KCa3.1 channel functions have been linked to abnormal cell proliferation, pathological tissue remodeling and fibrosis of a variety of organs, chronic inflammation, and autoimmune diseases (Wulff and Zhorov, 2008 ; Roach et al, 2013 ; Wulff and Köhler, 2013 ; Feske et al, 2015 ; Huang et al, 2015 ; Köhler et al, 2016 ). Accordingly, pharmacological inhibition of KCa3.1 has been suggested to be a treatment strategy for such disease states.…”

“…At this point, we would like to remind the reader that KCa3.1 functions in disease states have been so far related to pro-proliferative and -inflammatory processes and pathological organ remodeling such as kidney and lung fibrosis (Wulff and Zhorov, 2008 ; Roach et al, 2013 ; Wulff and Köhler, 2013 ; Feske et al, 2015 ; Huang et al, 2015 ; Köhler et al, 2016 ). Accordingly, pharmacological inhibition of KCa3.1 has been proposed as pharmacological strategy to treat chronic inflammation and organ fibrosis.…”

“…The intermediate-conductance calcium/calmodulin-gated potassium channel KCa3.1 (encoded by the KCNN4 gene) is expressed in a variety of tissues such red and white blood cell lineage, epithelia, and endothelia (Wei et al, 2005 ). Notably, induction of KCa3.1 is suspected to drive abnormal cell proliferation, inflammation, and pathological organ remodeling (fibrosis) in heart, kidneys, lungs, some cancers, and atherosclerosis and neo-angiogenesis (for review see: Roach et al, 2013 ; Feske et al, 2015 ; Huang et al, 2015 ; Köhler et al, 2016 ). Accordingly, pharmacological modulation of the channel is considered a way to treat disease in humans.…”

Pharmacologic targeting of endothelial Ca2+-activated K+ channels: A strategy to improve cardiovascular function

“…In the vasculature, KCa3.1 appears to be the predominant channel involved in agonist (e.g. acetylcholine, ACh) evoked EDH responses and vasodilation of resistance arteries [ 37 , 38 ]. In contrast, KCa2.3 channels have been implicated more in flow-induced dilatory responses and active hyperaemia [ 39 , 40 ].…”

Conditional KCa3.1-transgene induction in murine skin produces pruritic eczematous dermatitis with severe epidermal hyperplasia and hyperkeratosis

“…From the pathophysiological perspective, KCa3.1 induction has been implicated in several diseases states characterized by excessive cell proliferation and inflammation (For recent indepth reviews of KCa3.1 in health and as drug target in disease see [1,2,24]. For instance, induction of KCa3.1 was shown to regulate the phenotypic switch of fibroblasts and smooth muscle cells towards a dedifferentiated proliferative phenotype that promoted pathological organ remodeling in the lung, heart, and kidneys [25][26][27][28][29][30], as well as arterial neointima formation [18,31,32].…”