semaxinib and Cardiomegaly

Pulmonary hypertension (PH) is a disease of hyperplasia of pulmonary vascular cells. The pentose phosphate pathway (PPP)-a fundamental glucose metabolism pathway-is vital for cell growth. Because treatment of PH is inadequate, our goal was to determine whether inhibition of glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the PPP, prevents maladaptive gene expression that promotes smooth muscle cell (SMC) growth, reduces pulmonary artery remodeling, and normalizes hemodynamics in experimental models of PH. PH was induced in mice by exposure to 10% oxygen (Hx) or weekly injection of vascular endothelial growth factor receptor blocker [Sugen5416 (SU); 20 mg kg

Topics: Animals; Blood Pressure; Cardiomegaly; Cell Hypoxia; Cells, Cultured; DNA Methylation; Enzyme Inhibitors; Female; Glucosephosphate Dehydrogenase; Humans; Hypertension, Pulmonary; Indoles; Male; Mice; Mice, Inbred C57BL; Myocardium; Myocytes, Smooth Muscle; Pyrroles; Ventricular Function, Right

Our understanding of the pathophysiological basis of chronic thromboembolic pulmonary hypertension (CTEPH) will be accelerated by an animal model that replicates the phenotype of human CTEPH. Sprague-Dawley rats were administered a combination of a single dose each of plastic microspheres and vascular endothelial growth factor receptor antagonist in polystyrene microspheres (PE) + tyrosine kinase inhibitor SU5416 (SU) group. Shams received volume-matched saline; PE and SU groups received only microspheres or SU5416, respectively. PE + SU rats exhibited sustained pulmonary hypertension (62 ± 13 and 53 ± 14 mmHg at 3 and 6 weeks, respectively) with reduction of the ventriculoarterial coupling in vivo coincident with a large decrement in peak rate of oxygen consumption during aerobic exercise, respectively. PE + SU produced right ventricular hypokinesis, dilation, and hypertrophy observed on echocardiography, and 40% reduction in right ventricular contractile function in isolated perfused hearts. High-resolution computed tomographic pulmonary angiography and Ki-67 immunohistochemistry revealed abundant lung neovascularization and cellular proliferation in PE that was distinctly absent in the PE + SU group. We present a novel rodent model to reproduce much of the known phenotype of CTEPH, including the pivotal pathophysiological role of impaired vascular endothelial growth factor-dependent vascular remodeling. This model may reveal a better pathophysiological understanding of how PE transitions to CTEPH in human treatments.

Topics: Animals; Cardiomegaly; Cell Proliferation; Chronic Disease; Heart Function Tests; Hemodynamics; Hyperplasia; Hypertension, Pulmonary; Hypoxia; Indoles; Ki-67 Antigen; Lung; Male; Microspheres; Oxygen Consumption; P-Selectin; Partial Pressure; Physical Conditioning, Animal; Plasminogen Activator Inhibitor 1; Polystyrenes; Pulmonary Embolism; Pyrroles; Rats, Sprague-Dawley; Tissue Inhibitor of Metalloproteinase-1; Vascular Endothelial Growth Factor A; Ventricular Dysfunction