Abstract
There are two primary components that produce pulmonary arterial hypertension (PAH); aberrant structural changes (smooth muscle cell proliferation, smooth muscle cell hypertrophy, and the deposition of matrix proteins within the media of pulmonary arterial vessels), and excess vasoconstriction. However, in PAH, the target and aim of all current therapeutic agents is to reduce the contractility of the pulmonary vasculature; prostaglandins, phosphodiesterase inhibitors, guanylate cyclase stimulators, endothelin antagonists, NO inhalation and Rho kinase inhibitors all influence signaling pathways in the pulmonary vascular smooth muscle to decrease vasoconstriction, and hence, pulmonary vascular resistance (PVR). This review will therefore primarily focus on discussing the signaling pathways regulating contractility in pulmonary vascular smooth muscle, the mechanism for current treatments, as well as highlighting potential targets for the development of novel therapies.
Highlights
No animal model completely replicates pulmonary arterial hypertension (PAH), the mechanism(s) that produce PAH has been investigated using a number of different models, including chronic hypoxia, hypoxia combined with the vascular endothelial growth factor (VEGF) antagonist SU5146, monocrotaline (MCT), and the BMP4 KO
In both PAH and cancer, pyruvate dehydrogenase kinase (PDK) is elevated, and this enzyme is responsible for phosphorylation and inhibition of pyruvate dehydrogenase (PDH), a vital enzyme regulating the rate of oxidative metabolism
Most Bone Morphogenetic Protein Receptor Type 2 (BMPR2) mutations associated with PAH lead to abnormal SMAD signaling, which suppresses apoptosis resulting in proliferation of vascular cells
Summary
Pulmonary hypertension (PH) is defined as a resting mean pulmonary artery pressure (PAP) >25 mmHg. This disease results from progressive changes in the pulmonary vascular bed that increase pulmonary artery pressures, which leads to right ventricular (RV) failure This broad diagnosis includes patients with intrinsic pulmonary disease, and those with elevated pulmonary pressures related to left ventricular disease and high output heart failure. Once elevated pulmonary pressures have been detected on TTE, other tests are necessary to help delineate and categorize the type of PH These tests include pulmonary function testing to evaluate for underlying lung disease, screening overnight oximetry to assess for obstructive sleep apnea, ventilation-perfusion lung scintigraphy to rule out chronic thromboembolic PH, and a laboratory evaluation to screen for HIV, connective tissue disease, and underlying liver dysfunction. It is important to recognize that only 10–20% of patients with PAH illustrate any significant vasodilatory response to nitric oxide (Barst et al, 2004; McGoon et al, 2004)
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