Heparin Cofactor II Protects Against Angiotensin II-Induced Cardiac Remodeling Via Attenuation of Oxidative Stress in Mice

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-beta 1 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-beta 1 pathway. (Hypertension. 2010;56:430-436.)