Abstract 3218: Exacerbation of Angiotensin II-induced Cardiac Remodeling Through Enhancement of NADPH Oxidase - TGF-β 1 Pathway in Heparin Cofactor II-Deficient Mice
(Background) Heparin cofactor II (HCII) is a serine protease inhibitor that inhibits tissue thrombin action when bound to dermatan sulfate deposited in the extracellular matrix of the cardiovascular system. Although we previously reported that heterozygous HCII deficiency causes exaggerated vascular remodeling (J Clin Invest 2007:117; 1514 –26), the action of HCII on cardiac remodeling remains to be determined.
(Methods and Results) HCII+/+ and HCII+/− mice at 25 weeks of age were infused with angiotensin II (Ang II) (2.0 mg/kg/day) for 2 weeks by an osmotic mini-pump. Echocardiography revealed acceleration of cardiac concentric remodeling in HCII+/− mice and larger left atrial volume (LAV) in HCII+/− mice than in HCII+/+ mice (HCII+/+ vs HCII+/−, relative wall thickness: 0.48+/−0.03 vs 0.58+/−0.04, p<0.05, LAV: 6.8+/−1.2 vs 10.3+/−1.4μl, p<0.05). Histopathological studies showed prominent interstitial and perivascular fibrosis in both the left atrium and ventricle in HCII+/− mice. Daily urinary excretion of 8-OHdG, a parameter of oxidative stress, in HCII+/− mice was significantly greater than that in HCII+/+ mice (1.1+/−0.2 vs 1.6+/−0.3 ng/day/g body weight, p<0.05). In addition, expression of protease-activated receptor-1, one of the major thrombin receptors, and DHE-positive spots indicating superoxide production in the myocardium were markedly increased in Ang II-treated HCII+/− mice compared to those in Ang II-treated HCII+/+ mice. Cardiac gene expression levels of NOX4, p67 phox, rac-1, components of NADPH oxidase, and subsequent cardiac remodeling factor TGF-β 1 were much higher in Ang II-treated HCII+/− mice than in Ang II-treated HCII+/+ mice, and human HCII protein administration restored all of those abnormalities in Ang II-treated HCII+/− mice.
(Conclusion) HCII prevents the development of Ang II-induced cardiac remodeling through suppression of the NADPH oxidase-TGF-β1 pathway.