title: Docosahexaenoic acid causes rapid pulmonary arterial relaxation via KCa channel-mediated hyperpolarisation in pulmonary hypertension.
abstract: Cardioprotective benefits of ω-3 fatty acids such as docosahexaenoic acid (DHA) are well established, but the regulatory effect of DHA on vascular tone and pressure in pulmonary hypertension is largely unknown.As DHA is a potent regulator of K+channels, we hypothesised that DHA modulates the membrane potential of pulmonary artery smooth muscle cells (PASMCs) through K+channels and thus exerts its effects on pulmonary vascular tone and pressure.We show that DHA caused dose-dependent activation of the calcium-activated K+(KCa) current in primary human PASMCs and endothelium-dependent relaxation of pulmonary arteries. This vasodilation was significantly diminished in KCa-/-(Kcnma1-/-) mice. In vivo, acute DHA returned the right ventricular systolic pressure in the chronic hypoxia-induced pulmonary hypertension animal model to the level of normoxic animals. Interestingly, in idiopathic pulmonary arterial hypertension the KCa channels and their subunits were upregulated. DHA activated KCa channels in these human PASMCs and hyperpolarised the membrane potential of the idiopathic pulmonary arterial hypertension PASMCs to that of the PASMCs from healthy donors.Our findings indicate that DHA activates PASMC KCa channels leading to vasorelaxation in pulmonary hypertension. This effect might provide a molecular explanation for the previously undescribed role of DHA as an acute vasodilator in pulmonary hypertension.
authors.affiliation: Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria Experimental Anesthesiology, Dept of Anesthesia and Intensive Care Medicine, Medical University of Graz, Graz, Austria.
authors.forename: Chandran
authors.initials: C
authors.lastname: Nagaraj
authors.affiliation: Experimental Anesthesiology, Dept of Anesthesia and Intensive Care Medicine, Medical University of Graz, Graz, Austria Dept of Cardiovascular Medicine, The First Affiliated Hospital of Bengbu Medical College, Bengbu Anhui, PR China.
authors.forename: Bi
authors.initials: B
authors.lastname: Tang
authors.affiliation: Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria Institute of Physiology, Medical University of Graz, Graz, Austria.
authors.forename: Bence M
authors.initials: BM
authors.lastname: Nagy
authors.affiliation: Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria.
authors.forename: Rita
authors.initials: R
authors.lastname: Papp
authors.affiliation: Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria.
authors.forename: Pritesh P
authors.initials: PP
authors.lastname: Jain
authors.affiliation: Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria.
authors.forename: Leigh M
authors.initials: LM
authors.lastname: Marsh
authors.affiliation: Dept of Physiology, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Meredith
authors.affiliation: Division of Thoracic Surgery, Dept of Surgery, Medical University of Vienna, Vienna, Austria.
authors.forename: Bahil
authors.initials: B
authors.lastname: Ghanim
authors.affiliation: Division of Thoracic Surgery, Dept of Surgery, Medical University of Vienna, Vienna, Austria.
authors.forename: Walter
authors.initials: W
authors.lastname: Klepetko
authors.affiliation: Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria Experimental Anesthesiology, Dept of Anesthesia and Intensive Care Medicine, Medical University of Graz, Graz, Austria.
authors.forename: Grazyna
authors.initials: G
authors.lastname: Kwapiszewska
authors.affiliation: Dept of Medicine, University of Minnesota, Minneapolis, MN, USA.
authors.forename: E Kenneth
authors.initials: EK
authors.lastname: Weir
authors.affiliation: Division of Pulmonology, Dept of Internal Medicine, Medical University of Graz, Graz, Austria.
authors.forename: Horst
authors.initials: H
authors.lastname: Olschewski
authors.affiliation: Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria Institute of Physiology, Medical University of Graz, Graz, Austria andrea.olschewski@lvr.lbg.ac.at.
authors.forename: Andrea
authors.initials: A
authors.lastname: Olschewski
mesh_terms: D000328:Adult; D000818:Animals; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D065627:Familial Primary Pulmonary Hypertension / Q000503:physiopathology; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000503:physiopathology; D000860:Hypoxia / Q000503:physiopathology; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects*; D010477:Perfusion; D011651:Pulmonary Artery / Q000187:drug effects* / Q000503:physiopathology; D014664:Vasodilation
chemical_list: C494841:KCNMA1 protein, human; C465449:Kcnma1 protein, mouse; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D004281:Docosahexaenoic Acids