title: Heparin cofactor II protects against angiotensin II-induced cardiac remodeling via attenuation of oxidative stress in mice.
abstract: Heparin cofactor II (HCII), a serine protease inhibitor, inhibits tissue thrombin action after binding with dermatan sulfate proteoglycans in the extracellular matrix of the vascular system. We previously reported that heterozygous HCII-deficient (HCII(+/-)) humans and mice demonstrate acceleration of vascular remodeling, including atherosclerosis. However, the action of HCII on cardiac remodeling never has been determined. HCII(+/+) and HCII(+/-) mice at age 25 weeks were infused with angiotensin II (Ang II; 2.0 mg/kg/d) for 2 weeks by an osmotic mini-pump. Echocardiography revealed acceleration of cardiac concentric remodeling in HCII(+/-) mice and larger left atrial volume in HCII(+/-) mice than in HCII(+/+) mice. Histopathologic studies showed more prominent interstitial fibrosis in both the left atrium and left ventricle in HCII(+/-) mice than in HCII(+/+) mice. Daily urinary excretion of 8-hydroxy-2'-deoxyguanosine, a parameter of oxidative stress, and dihydroethidium-positive spots, indicating superoxide production in the myocardium, were markedly increased in Ang II-treated HCII(+/-) mice compared to those in HCII(+/+) mice. Cardiac gene expression levels of atrial natriuretic peptides and brain natriuretic peptides, members of the natriuretic peptide family, Nox 4, Rac-1, and p67(phox) as components of NAD(P)H oxidase, and transforming growth factor-beta1 and procollagen III were more augmented in HCII(+/-) mice than in HCII(+/+) mice. However, administration of human HCII protein attenuated all of those abnormalities in Ang II-treated HCII(+/-) mice. Moreover, human HCII protein supplementation almost abolished cardiac fibrosis in Ang II-treated HCII(+/+) mice. The results indicate that HCII has a protective role against Ang II-induced cardiac remodeling through suppression of the NAD(P)H oxidase-transforming growth factor-beta1 pathway.
authors.affiliation: Department of Medicine and Bioregulatory Sciences, The University of Tokushima Graduate School of Health Biosciences, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Sumitomo-Ueda
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Aihara
authors.forename: Takayuki
authors.initials: T
authors.lastname: Ise
authors.forename: Sumiko
authors.initials: S
authors.lastname: Yoshida
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Ikeda
authors.forename: Ryoko
authors.initials: R
authors.lastname: Uemoto
authors.forename: Shusuke
authors.initials: S
authors.lastname: Yagi
authors.forename: Takashi
authors.initials: T
authors.lastname: Iwase
authors.forename: Kazue
authors.initials: K
authors.lastname: Ishikawa
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Hirata
authors.forename: Masashi
authors.initials: M
authors.lastname: Akaike
authors.forename: Masataka
authors.initials: M
authors.lastname: Sata
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Kato
authors.forename: Toshio
authors.initials: T
authors.lastname: Matsumoto
mesh_terms: D000704:Analysis of Variance; D000804:Angiotensin II / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000378:metabolism; D006332:Cardiomegaly / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D004452:Echocardiography; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology; D006325:Heart Atria / Q000378:metabolism / Q000473:pathology; D015844:Heparin Cofactor II / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D020097:Natriuretic Peptide, Brain / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects* / Q000235:genetics; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D020257:Ventricular Remodeling / Q000187:drug effects* / Q000235:genetics
chemical_list: D053773:Transforming Growth Factor beta1; D000804:Angiotensin II; D020097:Natriuretic Peptide, Brain; D015844:Heparin Cofactor II; D009320:Atrial Natriuretic Factor