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Granzyme B deficiency promotes osteoblastic differentiation and calcification of vascular smooth muscle cells in hypoxic pulmonary hypertension.

ABSTRACT: Calcification is a major risk factor for vascular integrity. This pathological symptom and the underlying mechanisms in hypoxic pulmonary artery hypertension remain elusive. Here we report that pulmonary vascular medial calcification is elevated in pulmonary artery hypertension models as a result of an osteoblastic phenotype change of pulmonary arterial smooth muscle cells induced by hypoxia. Notably, inhibiting store-operated calcium channels significantly decreased osteoblastic differentiation and calcification of pulmonary arterial smooth muscle cells under hypoxia. We identified granzyme B, a major constituent of cytotoxic T lymphocytes/natural killer cell granules involved in apoptosis, as the main regulator of pulmonary arterial calcification. Overexpression of granzyme B blocked the mineralization through its effect on store-operated calcium channels in cultured pulmonary arterial smooth muscle cells under hypoxic conditions. Mice with overexpression of granzyme B exposed to hypoxia for 3 weeks showed attenuated vascular calcification and pathological progression of hypoxic pulmonary arterial hypertension. Our findings emphasize the central function of granzyme B in coordinating vascular calcification in hypoxic pulmonary arterial hypertension.

SUBMITTER: Mao M

PROVIDER: S-EPMC5833422 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Granzyme B deficiency promotes osteoblastic differentiation and calcification of vascular smooth muscle cells in hypoxic pulmonary hypertension.

Mao Min M Zhang Min M Ge Anqi A Ge Xin X Gu Rui R Zhang Chen C Fu Yao Y Gao Jiayin J Wang Xiaoying X Liu Yang Y Zhu Daling D

Cell death & disease 20180214 2

Calcification is a major risk factor for vascular integrity. This pathological symptom and the underlying mechanisms in hypoxic pulmonary artery hypertension remain elusive. Here we report that pulmonary vascular medial calcification is elevated in pulmonary artery hypertension models as a result of an osteoblastic phenotype change of pulmonary arterial smooth muscle cells induced by hypoxia. Notably, inhibiting store-operated calcium channels significantly decreased osteoblastic differentiation ...[more]

PMID: 29445095

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Project description:Rationale: Glycolytic shift is implicated in the pathogenesis of pulmonary arterial hypertension (PAH). It remains unknown how glycolysis is increased and how increased glycolysis contributes to pulmonary vascular remodeling in PAH.Objectives: To determine whether increased glycolysis is caused by 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) and how PFKFB3-driven glycolysis induces vascular remodeling in PAH.Methods: PFKFB3 levels were measured in pulmonary arteries of patients and animals with PAH. Lactate levels were assessed in lungs of animals with PAH and in pulmonary artery smooth muscle cells (PASMCs). Genetic and pharmacologic approaches were used to investigate the role of PFKFB3 in PAH.Measurements and Main Results: Lactate production was elevated in lungs of PAH rodents and in platelet-derived growth factor-treated PASMCs. PFKFB3 protein was higher in pulmonary arteries of patients and rodents with PAH, in PASMCs of patients with PAH, and in platelet-derived growth factor-treated PASMCs. PFKFB3 inhibition by genetic disruption and chemical inhibitor attenuated phosphorylation/activation of extracellular signal-regulated kinase (ERK1/2) and calpain-2, and vascular remodeling in PAH rodent models, and reduced platelet-derived growth factor-induced phosphorylation/activation of ERK1/2 and calpain-2, collagen synthesis and proliferation of PASMCs. ERK1/2 inhibition attenuated phosphorylation/activation of calpain-2, and vascular remodeling in Sugen/hypoxia PAH rats, and reduced lactate-induced phosphorylation/activation of calpain-2, collagen synthesis, and proliferation of PASMCs. Calpain-2 inhibition reduced lactate-induced collagen synthesis and proliferation of PASMCs.Conclusions: Upregulated PFKFB3 mediates collagen synthesis and proliferation of PASMCs, contributing to vascular remodeling in PAH. The mechanism is through the elevation of glycolysis and lactate that results in the activation of calpain by ERK1/2-dependent phosphorylation of calpain-2.

Dataset Information

Granzyme B deficiency promotes osteoblastic differentiation and calcification of vascular smooth muscle cells in hypoxic pulmonary hypertension.

Publications

Granzyme B deficiency promotes osteoblastic differentiation and calcification of vascular smooth muscle cells in hypoxic pulmonary hypertension.

Similar Datasets

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