Parathyroid Hormone Contributes to Pulmonary Hypertension in Hypoxic Conditions

Pulmonary hypertension (PH) is characterized by increased pulmonary artery pressure and can lead to right heart failure. Parathyroid hormone (PTH) is secreted by the parathyroid gland and plays a crucial role in calcium homeostasis. PTH also acts on the cardiovascular system and affects cardiovascular prognosis. We hypothesized that PTH would play a potential role in the pathogenesis of PH.

Serum PTH levels were measured in patients with PH or suspected PH who underwent evaluation using right heart catheterization. We assessed whether the regulation of PTH and the PTH1R (PTH receptor) affected PH in a hypoxia-induced PH mouse model and a Sugen/hypoxia-induced PH rat model. To examine PTH1R regulation and the direct effects of PTH, human pulmonary artery smooth muscle cells were cultured.

In the clinical study, we found that serum PTH concentration was associated with both mean pulmonary artery pressure and pulmonary vascular resistance, with a cutoff PTH level of 46.0 pg/mL (68.2% sensitivity, 100% specificity) for predicting PH. In the PH animal models-Sugen/hypoxia rats and hypoxia mice-PTH treatment exacerbated right ventricular hypertrophy and right ventricular systolic pressure. Conversely, PTH reduction by parathyroidectomy attenuated right ventricular hypertrophy and reduced pulmonary vascular remodeling in Sugen/hypoxia rats. In vitro studies revealed that HIF1α (hypoxia-inducible factor-1 alpha) promoted the PTH1R. Moreover, knockdown of the PTH receptor in the lungs ameliorated PH in Sugen/hypoxia rats and hypoxia mice. Treatment with PTH increased proliferation and migration of pulmonary artery smooth muscle cells through the PTH receptor-β-arrestin-ERK (extracellular signal-regulated kinase) signaling axis.

Our clinical and experimental data suggest a potential involvement of PTH/PTH1R signaling in the development and progression of PH, highlighting PTH1R as a possible therapeutic target for further investigation.