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

Abstract

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 ϩ/Ϫ ) humans and mice demonstrate acceleration of vascular remodeling, including atherosclerosis. However, the action of HCII on cardiac remodeling never has been determined. HCII ϩ/ϩ and HCII ϩ/Ϫ 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 ϩ/Ϫ mice and larger left atrial volume in HCII ϩ/Ϫ mice than in HCII ϩ/ϩ mice. Histopathologic studies showed more prominent interstitial fibrosis in both the left atrium and left ventricle in HCII ϩ/Ϫ mice than in HCII ϩ/ϩ mice. Daily urinary excretion of 8-hydroxy-2Ј-deoxyguanosine, a parameter of oxidative stress, and dihydroethidium-positive spots, indicating superoxide production in the myocardium, were markedly increased in Ang II-treated HCII ϩ/Ϫ mice compared to those in HCII ϩ/ϩ 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-␤1 and procollagen III were more augmented in HCII ϩ/Ϫ mice than in HCII ϩ/ϩ mice. However, administration of human HCII protein attenuated all of those abnormalities in Ang II-treated HCII ϩ/Ϫ mice. Moreover, human HCII protein supplementation almost abolished cardiac fibrosis in Ang II-treated HCII ϩ/ϩ 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-␤1 pathway. (Hypertension. 2010;56:430-436.)

Paricalcitol modulates ACE2 shedding and renal ADAM17 in NOD mice beyond proteinuria

“…Another beneficial effect of paricalcitol is that it activates both antihypertrophic and antifibrotic activity in a murine model of cardiac hypertrophy and fibrosis generated by chronic infusion of ANG II (7,15,43). Accordingly, in our model, animals given paricalcitol showed significant reductions in heart/body weight ratios compared with other diabetic animals.…”

Heparin Cofactor II, a Serine Protease Inhibitor, Promotes Angiogenesis via Activation of the AMP-activated Protein Kinase-Endothelial Nitric-oxide Synthase Signaling Pathway

“…In experimental animal studies, we and Vicente et al revealed that HCII-deficient mice showed more prominent intimal hyperplasia after vascular injury than did in wild-type (WT) littermates (11,12). In addition, plasma HCII activity is inversely associated with acceleration of human and murine cardiac remodeling including atrial enlargement and left ventricular concentric alteration (13,14). These findings revealed that HCII plays a protective role in the development of vascular remodeling and cardiac remodeling in humans and mice.…”

“…HCII ϩ/Ϫ mice were backcrossed for 10 generations with the C57BL/6J strain (12). Because our homozygote HCIIdeficient mice were embryonically lethal, we used male heterozygote HCII-deficient (HCII ϩ/Ϫ ) mice and male littermate WT (HCII ϩ/ϩ ) mice in all experiments of this study as in our previous studies (12,14). Our HCII ϩ/Ϫ mice showed approximately half of the plasma HCII activity of littermate WT mice, and there is no obviously different phenotype in either HCII ϩ/ϩ mice or HCII ϩ/Ϫ mice at base line (12).…”

Plasma heparin cofactor II activity is inversely associated with left atrial volume and diastolic dysfunction in humans with cardiovascular risk factors

“…41 In that study, infusion of angiotensin II prominently accelerated cardiac remodeling, including concentric LV changes, enlargement of LAV and exaggeration of cardiac fibrosis in HCII-deficient mice when compared with littermate wild-type mice. 41 The study using HCII-deficient mice demonstrated that HCII protects against angiotensin II-induced cardiac remodeling through the suppression of the NAD(P)H oxidase-TGF-b1 pathway. 41 Therefore, we speculate that HCII is also capable of attenuating oxidative stress in the human heart, as well as in the murine heart through suppression of the NAD(P)H oxidase-TGF-b1 pathway.…”

“…41 The study using HCII-deficient mice demonstrated that HCII protects against angiotensin II-induced cardiac remodeling through the suppression of the NAD(P)H oxidase-TGF-b1 pathway. 41 Therefore, we speculate that HCII is also capable of attenuating oxidative stress in the human heart, as well as in the murine heart through suppression of the NAD(P)H oxidase-TGF-b1 pathway.…”