propylthiouracil and Hypertension--Pulmonary

Topics: Adult; Antithyroid Agents; Computed Tomography Angiography; Conservative Treatment; Echocardiography, Transesophageal; Electrocardiography; Female; Graves Disease; Heart Failure; Humans; Hypertension, Pulmonary; Image Processing, Computer-Assisted; Methimazole; Propylthiouracil; Scimitar Syndrome; Thyroid Function Tests; Treatment Outcome; Tricuspid Valve Insufficiency; Vena Cava, Inferior

Gamma-secretase-mediated Notch3 signaling is involved in smooth muscle cell (SMC) hyper-activity and proliferation leading to pulmonary arterial hypertension (PAH). In addition, Propylthiouracil (PTU), beyond its anti-thyroid action, has suppressive effects on atherosclerosis and PAH. Here, we investigated the possible involvement of gamma-secretase-mediated Notch3 signaling in PTU-inhibited PAH. In rats with monocrotaline-induced PAH, PTU therapy improved pulmonary arterial hypertrophy and hemodynamics. In vitro, treatment of PASMCs from monocrotaline-treated rats with PTU inhibited their proliferation and migration. Immunocyto, histochemistry, and western blot showed that PTU treatment attenuated the activation of Notch3 signaling in PASMCs from monocrotaline-treated rats, which was mediated via inhibition of gamma-secretase expression especially its presenilin enhancer 2 (Pen-2) subunit. Furthermore, over-expression of Pen-2 in PASMCs from control rats increased the capacity of migration, whereas knockdown of Pen-2 with its respective siRNA in PASMCs from monocrotaline-treated rats had an opposite effect. Transfection of PASMCs from monocrotaline-treated rats with Pen-2 siRNA blocked the inhibitory effect of PTU on PASMC proliferation and migration, reflecting the crucial role of Pen-2 in PTU effect. We present a novel cell-signaling paradigm in which overexpression of Pen-2 is essential for experimental pulmonary arterial hypertension to promote motility and growth of smooth muscle cells. Propylthiouracil attenuates experimental PAH via suppression of the gamma-secretase-mediated Notch3 signaling especially its presenilin enhancer 2 (Pen-2) subunit. These findings provide a deep insight into the pathogenesis of PAH and a novel therapeutic strategy.

Topics: Amyloid Precursor Protein Secretases; Animals; Cell Movement; Cell Proliferation; Cells, Cultured; Disease Models, Animal; Gene Expression; Hypertension, Pulmonary; Lung; Male; Presenilin-2; Propylthiouracil; Rats, Sprague-Dawley; Receptor, Notch3; Receptors, Notch; Signal Transduction

Propylthiouracil (PTU) enhances nitric oxide production and inhibits smooth muscle cell proliferation, suggesting a possible role in the prevention of pulmonary arterial hypertension (PAH).. The 30 male Sprague-Dawley rats were randomized to receive saline injection only (group 1), monocrotaline (MCT) (70 mg/kg) only (group 2) or MCT + 0.1% PTU in drinking water (group 3) given on day 5 after MCT administration. By day 35, western blot showed lower connexin43 (Cx43) and membranous protein kinase C-epsilon expressions in the right ventricle (RV) of group 2 animals than in the other groups (all P<0.05). Conversely, Cx43 expression in the lung was higher in group 2 than in other groups (all P<0.02). Additionally, mRNA expressions of matrix metalloproteinase-9, tissue necrotic factor-alpha, and caspase-3 were higher, whereas Bcl-2 and endothelial nitric oxide synthase were lower, in the lungs and RV of group 2 rats than in the other groups (all P<0.05). Moreover, the numbers of alveolar sacs and lung arterioles were also reduced in group 2 than in other groups (all P<0.05), and RV systolic pressure and RV weight were increased in group 2 compared with other groups (all P<0.001).. PTU effectively attenuates complications associated with MCT-induced PAH.

Topics: Animals; Antihypertensive Agents; Arterioles; Caspase 3; Connexin 43; Disease Models, Animal; Heart Ventricles; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Lung; Male; Matrix Metalloproteinase 9; Monocrotaline; Nitric Oxide Synthase Type III; Propylthiouracil; Protein Kinase C-epsilon; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Sprague-Dawley; RNA, Messenger; Time Factors; Tumor Necrosis Factor-alpha; Ventricular Function, Right; Ventricular Pressure

Recent reports suggest an association between hyperthyroidism and pulmonary hypertension (PHT), although the potential mechanisms and clinical implications remain unclear.. Our objective was to determine the prevalence of PHT related to hyperthyroidism and the associated hemodynamic changes and outcome.. We performed serial echocardiographic examinations in 75 consecutive patients with hyperthyroidism (43 +/- 2 yr, 47 women) to estimate pulmonary artery systolic pressure (PASP), cardiac output (CO), total vascular resistance (TVR), and left ventricular (LV) filling pressure. Examinations were performed at baseline and 6 months after initiation of antithyroid treatment. Results were compared with 35 age- and sex-matched healthy controls. All hyperthyroid patients had normal LV systolic function, and 35 patients (47%) had PHT with PASP of at least 35 mm Hg. There were no significant differences in the clinical characteristics of hyperthyroid patients with or without PHT (all P > 0.05). Nonetheless, those with PHT had significantly higher CO, PASP, peak transmitral early diastolic flow velocity (E), and ratio of E to early diastolic mitral annular velocity (E') compared with those without PHT and controls (all P < 0.05). Hyperthyroid patients with PHT also had significantly lower TVR than controls (P < 0.05). Among the 35 hyperthyroid patients with PHT, 25 (71%) had pulmonary arterial hypertension (PAH) with normal E/E', and 10 (29%) had pulmonary venous hypertension (PVH) with elevated E/E'. Hyperthyroid patients with PAH had a significantly higher CO and a lower TVR compared with those with PVH. In contrast, hyperthyroid patients with PVH had lower E' and a higher E/E' ratio compared with those with PAH. These hemodynamic abnormalities and PHT were reversible in patients with PAH or PVH after restoration to a euthyroid state.. In patients with hyperthyroidism and normal LV systolic function, up to 47% had PHT due to either PAH with increased CO (70%) or PVH with elevated LV filling pressure (30%). Most importantly, hyperthyroidism-related PHT was largely asymptomatic and reversible after restoration to a euthyroid state.

Topics: Adult; Antithyroid Agents; Blood Pressure; Carbimazole; Cardiac Output; Echocardiography; Echocardiography, Doppler; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Hyperthyroidism; Male; Middle Aged; Propylthiouracil; Prospective Studies; Treatment Outcome; Vascular Resistance; Ventricular Function, Left

We describe a case of pulmonary hypertension and high-output heart failure in a 61-year-old woman suffering from relapsing Graves disease. The patient experienced prompt hemodynamic and symptomatic recovery after normal thyroid function was restored. Possible mechanisms for the development of pulmonary arterial hypertension due to hyperthyroidism include damage to pulmonary vascular endothelium due to high cardiac output or an autoimmune process or increased metabolism of intrinsic pulmonary vasodilators. Another possible mechanism is vascular vasoconstriction due to decreased cholinergic output.

Topics: Antihypertensive Agents; Antithyroid Agents; Female; Humans; Hypertension, Pulmonary; Hyperthyroidism; Middle Aged; Propranolol; Propylthiouracil