Superoxide dismutase/catalase mimetic EUK-134 prevents diaphragm muscle weakness in monocrotalin-induced pulmonary hypertension.
Patients with pulmonary hypertension (PH) suffer from inspiratory insufficiency, which has been associated with intrinsic contractile dysfunction in diaphragm muscle. Here, we examined the role of redox stress in PH-induced diaphragm weakness by using the novel antioxidant, EUK-134. Male Wistar rats were randomly divided into control (CNT), CNT + EUK-134 (CNT + EUK), monocrotaline-induced PH (PH), and PH + EUK groups. PH was induced by a single intraperitoneal injection of monocrotaline (60 mg/kg body weight). EUK-134 (3 mg/kg body weight/day), a cell permeable mimetic of superoxide dismutase (SOD) and catalase, was daily intraperitoneally administered starting one day after induction of PH. After four weeks, diaphragm muscles were excised for mechanical and biochemical analyses. There was a decrease in specific tetanic force in diaphragm bundles from the PH group, which was accompanied by increases in: protein expression of NADPH oxidase 2/gp91phox, SOD2, and catalase; 3-nitrotyrosine content and aggregation of actin; glutathione oxidation. Treatment with EUK-134 prevented the force decrease and the actin modifications in PH diaphragm bundles. These data show that redox stress plays a pivotal role in PH-induced diaphragm weakness. Thus, antioxidant treatment can be a promising strategy for PH patients with inspiratory failure.
Graduate School of Health Sciences, Sapporo Medical University, Sapporo, Japan.
Koichi
K
Himori
Graduate School of Health Sciences, Sapporo Medical University, Sapporo, Japan.
Masami
M
Abe
Graduate School of Health Sciences, Sapporo Medical University, Sapporo, Japan.
Daisuke
D
Tatebayashi
Graduate School of Health Sciences, Sapporo Medical University, Sapporo, Japan.
Jaesik
J
Lee
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
Håkan
H
Westerblad
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
Johanna T
JT
Lanner
Graduate School of Health Sciences, Sapporo Medical University, Sapporo, Japan.
Takashi
http://orcid.org/0000-0003-1797-3880
T
Yamada
D000199:Actins / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D040761:Biomimetic Materials / Q000494:pharmacology; D002374:Catalase / Q000378:metabolism; D003964:Diaphragm / Q000187:drug effects / Q000503:physiopathology; D004195:Disease Models, Animal; D005978:Glutathione / Q000378:metabolism; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000503:physiopathology*; D008297:Male; D016686:Monocrotaline / Q000633:toxicity; D009119:Muscle Contraction / Q000187:drug effects; D018908:Muscle Weakness / Q000503:physiopathology / Q000517:prevention & control*; D009942:Organometallic Compounds / Q000494:pharmacology*; D018384:Oxidative Stress; D051381:Rats; D017208:Rats, Wistar; D012459:Salicylates / Q000494:pharmacology*; D013482:Superoxide Dismutase / Q000378:metabolism
D000199:Actins; D000975:Antioxidants; C433928:EUK-134; D009942:Organometallic Compounds; D012459:Salicylates; D016686:Monocrotaline; D002374:Catalase; D013482:Superoxide Dismutase; D005978:Glutathione