Does deficiency of smooth muscle Adar1 exacerbate vascular remodeling and pulmonary hypertension in mice?
Smooth muscle-specific ADAR1 deficiency exacerbates pulmonary hypertension and vascular remodeling via innate immune responses, suggesting PKR as a potential therapeutic target.
BACKGROUND: ADAR1 (adenosine deaminase acting on RNA 1) catalyzes the conversion of adenosine to inosine in double stranded RNAs (dsRNAs), which is critical to prevent autoinflammatory responses mediated by activation of the type I IFN (interferon) signaling. We define the role of ADAR1-dependent RNA editing in IFNβ activation in pulmonary arterial smooth muscle cells (PASMCs) from idiopathic pulmonary arterial hypertension (IPAH), a devastating disease leading to right heart failure and death. METHODS: selectively in Sma (smooth muscle actin)-expressing cells, followed by 3 weeks of hypoxic exposure to induce pulmonary hypertension (PH). RESULTS: mice. CONCLUSIONS: Our study describes a fundamental molecular mechanism underlying the progression of PH. We highlight the detrimental role of innate immune responses, where smooth muscle cell and context-specific RNA editing, along with the sensing of dsRNA, mediate disease progression and excessive vascular remodeling. This finding suggests that targeting PKR could be the new therapeutic strategy for treating pulmonary arterial hypertension.
Kim et al. (Wed,) studied this question.