Abstract 3158: Induction of HIF1α With Cobalt Chloride Induces Pulmonary Hypertension in vivo
Introduction: Pulmonary arterial hypertension (PAH) is a vascular disease characterized by obstruction of the pulmonary circulation and ultimately leads to right ventricular (RV) failure. Despite optimal treatment the incident 1-year mortality is 15%. HIF1α activation has been described in animal models and patients with PAH, however it is unknown whether HIF1α activation alone is sufficient to induce PAH.
Methods: Cobalt chloride (CoCl2) interferes with HIF1α breakdown and leads to nuclear HIF1α accumulation. Adult male Sprague Dawley rats were injected daily with water or with 8mg CoCl2/kg (n=7 in each group). Doppler echocardiography and high-fidelity cardiac catheterization were used to determine the pulmonary artery acceleration time and RV pressures. Heparanized blood was centrifuged to determine the hematocrit. RV hypertrophy was assessed as the ratio of RV to left ventricle plus septum weight. Muscularization was determined on paraffin-embedded lung sections after staining with vWF (Abcam) and SMC actin (MP Biomedicals).
Results: Hematocrit was elevated in CoCl2-treated rats versus controls (66±1 vs. 51±2%, P<0.01). Echocardiography revealed a decreased pulmonary artery acceleration time in rats receiving CoCl2 (22±1 vs. 33±2ms, P<0.01). Catheterization confirmed the presence of pulmonary hypertension (RV systolic pressure 36±4 vs. 22±1mmHg, P<0.01; pulmonary artery systolic pressure: 35±4 vs. 22±1 mmHg, P<0.01) and a reduction in cardiac output (81±7 vs. 147±13 ml/min). The RV fractional weight increased significantly in rats receiving daily CoCl2 injections versus controls (32±2 vs. 26±1%, P<0.05). A larger proportion of small pulmonary blood vessels (<50μm diameter) was muscularized in CoCl2-treated animals (81±4 vs. 44±5%, P<0.01) and their smooth muscle coat was thicker (16±1 vs. 7±1% of the total vessel diameter).
Conclusion: Daily treatment with the HIF1α activator CoCl2 for 4 weeks causes increased muscularization of the small pulmonary blood vessels, increased pulmonary pressures and RV hypertrophy. Our results confirm the important role of HIF1α in the development of pulmonary hypertension and are the first to demonstrate that signaling through HIF1α is sufficient to develop pulmonary hypertension.
This research has received full or partial funding support from the American Heart Association, Midwest Affiliate (Illinois, Indiana, Iowa, Kansas, Michigan, Minnesota, Missouri, Nebraska, North Dakota, South Dakota & Wisconsin).