Absence of the inflammasome adaptor ASC reduces hypoxia-induced pulmonary hypertension in mice

Fadila Telarevic Cero; Vigdis Hillestad; Ivar Sjaastad; Arne Yndestad; Pål Aukrust; Trine Ranheim; Ida Gjervold Lunde; Maria Belland Olsen; Egil Lien; Lili Zhang; Solveig Bjærum Haugstad; Else Marit Løberg; Geir Christensen; Karl-Otto Larsen; Ole Henning Skjønsberg

doi:10.1152/ajplung.00342.2014

Absence of the inflammasome adaptor ASC reduces hypoxia-induced pulmonary hypertension in mice

Am J Physiol Lung Cell Mol Physiol. 2015 Aug 15;309(4):L378-87. doi: 10.1152/ajplung.00342.2014. Epub 2015 Jun 12.

Authors

Affiliations

¹ Department of Pulmonary Medicine, Oslo University Hospital Ullevål and University of Oslo, Oslo, Norway; Institute for Experimental Medical Research, Oslo University Hospital Ullevål and University of Oslo, Oslo, Norway; Center for Heart Failure Research, Oslo University Hospital Ullevål and University of Oslo, Oslo, Norway; cero.fadila@medisin.uio.no.
² Institute for Experimental Medical Research, Oslo University Hospital Ullevål and University of Oslo, Oslo, Norway; Center for Heart Failure Research, Oslo University Hospital Ullevål and University of Oslo, Oslo, Norway;
³ Institute for Experimental Medical Research, Oslo University Hospital Ullevål and University of Oslo, Oslo, Norway; Center for Heart Failure Research, Oslo University Hospital Ullevål and University of Oslo, Oslo, Norway; K.G. Jebsen Inflammation Research Center, Faculty of Medicine, University of Oslo, Oslo, Norway;
⁴ Center for Heart Failure Research, Oslo University Hospital Ullevål and University of Oslo, Oslo, Norway; Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet and University of Oslo, Oslo, Norway; K.G. Jebsen Inflammation Research Center, Faculty of Medicine, University of Oslo, Oslo, Norway;
⁵ Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet and University of Oslo, Oslo, Norway; K.G. Jebsen Inflammation Research Center, Faculty of Medicine, University of Oslo, Oslo, Norway; Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet and University of Oslo, Oslo, Norway;
⁶ Institute for Experimental Medical Research, Oslo University Hospital Ullevål and University of Oslo, Oslo, Norway; Center for Heart Failure Research, Oslo University Hospital Ullevål and University of Oslo, Oslo, Norway; Department of Genetics, Harvard Medical School, Boston, Massachusetts;
⁷ Center for Heart Failure Research, Oslo University Hospital Ullevål and University of Oslo, Oslo, Norway; Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet and University of Oslo, Oslo, Norway;
⁸ Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts; Centre of Inflammation Research, Department of Cancer Research and Molecular Medicine, NTNU, Trondheim, Norway;
⁹ Department of Pathology, Oslo University Hospital Ullevål and University of Oslo, Oslo, Norway.
¹⁰ Department of Pulmonary Medicine, Oslo University Hospital Ullevål and University of Oslo, Oslo, Norway; Center for Heart Failure Research, Oslo University Hospital Ullevål and University of Oslo, Oslo, Norway;
¹¹ Department of Pulmonary Medicine, Oslo University Hospital Ullevål and University of Oslo, Oslo, Norway;

PMID: 26071556
DOI: 10.1152/ajplung.00342.2014

Abstract

Pulmonary hypertension is a serious condition that can lead to premature death. The mechanisms involved are incompletely understood although a role for the immune system has been suggested. Inflammasomes are part of the innate immune system and consist of the effector caspase-1 and a receptor, where nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 (NLRP3) is the best characterized and interacts with the adaptor protein apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC). To investigate whether ASC and NLRP3 inflammasome components are involved in hypoxia-induced pulmonary hypertension, we utilized mice deficient in ASC and NLRP3. Active caspase-1, IL-18, and IL-1β, which are regulated by inflammasomes, were measured in lung homogenates in wild-type (WT), ASC(-/-), and NLRP3(-/-) mice, and phenotypical changes related to pulmonary hypertension and right ventricular remodeling were characterized after hypoxic exposure. Right ventricular systolic pressure (RVSP) of ASC(-/-) mice was significantly lower than in WT exposed to hypoxia (40.8 ± 1.5 mmHg vs. 55.8 ± 2.4 mmHg, P < 0.001), indicating a substantially reduced pulmonary hypertension in mice lacking ASC. Magnetic resonance imaging further supported these findings by demonstrating reduced right ventricular remodeling. RVSP of NLRP3(-/-) mice exposed to hypoxia was not significantly altered compared with WT hypoxia. Whereas hypoxia increased protein levels of caspase-1, IL-18, and IL-1β in WT and NLRP3(-/-) mice, this response was absent in ASC(-/-) mice. Moreover, ASC(-/-) mice displayed reduced muscularization and collagen deposition around arteries. In conclusion, hypoxia-induced elevated right ventricular pressure and remodeling were attenuated in mice lacking the inflammasome adaptor protein ASC, suggesting that inflammasomes play an important role in the pathogenesis of pulmonary hypertension.

Keywords: inflammation; innate immunity; pulmonary vasculature.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis Regulatory Proteins / genetics*
Apoptosis Regulatory Proteins / metabolism
Arteries / pathology
CARD Signaling Adaptor Proteins
Cell Hypoxia
Collagen / metabolism
Gene Expression
Hypertension, Pulmonary / metabolism*
Hypertrophy, Right Ventricular / metabolism
Inflammasomes / metabolism*
Interleukin-18 / blood
Leukocytes / immunology
Lung / immunology
Lung / pathology
Male
Mice, Inbred C57BL
Mice, Knockout
Muscle, Smooth, Vascular / pathology
Ventricular Remodeling

Substances

Apoptosis Regulatory Proteins
CARD Signaling Adaptor Proteins
Inflammasomes
Interleukin-18
Pycard protein, mouse
Collagen