Elafin Reverses Pulmonary Hypertension via Caveolin-1-Dependent Bone Morphogenetic Protein Signaling.

Abstract

RATIONALE:

Pulmonary arterial hypertension is characterized by endothelial dysfunction, impaired bone morphogenetic protein receptor 2 (BMPR2) signaling, and increased elastase activity. Synthetic elastase inhibitors reverse experimental pulmonary hypertension but cause hepatotoxicity in clinical studies. The endogenous elastase inhibitor elafin attenuates hypoxic pulmonary hypertension in mice, but its potential to improve endothelial function and BMPR2 signaling, and to reverse severe experimental pulmonary hypertension or vascular pathology in the human disease was unknown.

OBJECTIVES:

To assess elafin-mediated regression of pulmonary vascular pathology in rats and in lung explants from patients with pulmonary hypertension. To determine if elafin amplifies BMPR2 signaling in pulmonary artery endothelial cells and to elucidate the underlying mechanism.

METHODS:

Rats with pulmonary hypertension induced by vascular endothelial growth factor receptor blockade and hypoxia (Sugen/hypoxia) as well as lung organ cultures from patients with pulmonary hypertension were used to assess elafin-mediated reversibility of pulmonary vascular disease. Pulmonary arterial endothelial cells from patients and control subjects were used to determine the efficacy and mechanism of elafin-mediated BMPR2 signaling.

MEASUREMENTS AND MAIN RESULTS:

In Sugen/hypoxia rats, elafin reduced elastase activity and reversed pulmonary hypertension, judged by regression of right ventricular systolic pressure and hypertrophy and pulmonary artery occlusive changes. Elafin improved endothelial function by increasing apelin, a BMPR2 target. Elafin induced apoptosis in human pulmonary arterial smooth muscle cells and decreased neointimal lesions in lung organ culture. In normal and patient pulmonary artery endothelial cells, elafin promoted angiogenesis by increasing pSMAD-dependent and -independent BMPR2 signaling. This was linked mechanistically to augmented interaction of BMPR2 with caveolin-1 via elafin-mediated stabilization of endothelial surface caveolin-1.

CONCLUSIONS:

Elafin reverses obliterative changes in pulmonary arteries via elastase inhibition and caveolin-1-dependent amplification of BMPR2 signaling.

• Authors: Nils P Nickel, Edda Spiekerkoetter, Mingxia Gu, Caiyun G Li, Hai Li, Mark Kaschwich, Isabel Diebold, Jan K Hennigs, Ki-Yoon Kim, Kazuya Miyagawa, Lingli Wang, Aiqin Cao, Silin Sa, Xinguo Jiang, Raymond W Stockstill, Mark R Nicolls, Roham T Zamanian, Richard D Bland, Marlene Rabinovitch
• Journal: American journal of respiratory and critical care medicine (Am J Respir Crit Care Med) Vol. 191 Issue 11 Pg. 1273-86 (Jun 01 2015) ISSN: 1535-4970 [Electronic] United States
• PMID: 25853696 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Caveolin 1
• Elafin
• Protease Inhibitors
• Bone Morphogenetic Protein Receptors, Type II
• Pancreatic Elastase

Topics

• Animals
• Apoptosis (drug effects)
• Bone Morphogenetic Protein Receptors, Type II (drug effects)
• Caveolin 1 (drug effects)
• Cells, Cultured
• Elafin (pharmacology)
• Endothelial Cells (drug effects)
• Humans
• Hypertension, Pulmonary (drug therapy)
• Myocytes, Smooth Muscle (drug effects)
• Pancreatic Elastase (drug effects)
• Protease Inhibitors (pharmacology)
• Rats
• Signal Transduction (drug effects)