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

作者：Cero Fadila Telarevic^*; Hillestad Vigdis; Sjaastad Ivar; Yndestad Arne; Aukrust PaL; Ranheim Trine; Lunde Ida Gjervold; Olsen Maria Belland; Lien Egil; Zhang Lili; Haugstad Solveig Bjaerum; Loberg Else Marit; Christensen Geir; Larsen Karl Otto; Skjon**erg Ole Henning

来源：American Journal of Physiology - Lung Cellular and Molecular Physiology, 2015, 309(4): L378-L387.

DOI：10.1152/ajplung.00342.2014

• inflammation
• innate immunity
• pulmonary vasculature

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-1 beta, 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-1 beta 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.

• 出版日期2015-8-15