Scholarlink

<p>Pulmonary arterial hypertension (PAH) is a life-threatening metabolic disorder. Nuclear receptors REV-ERBα and REV-ERBβ are established regulators of circadian rhythm and metabolic homeostasis, however their roles in PAH remain unclear. Using <i>Rev-erbα</i><sup>+/-</sup>, VSMC-specific <i>Rev-erbα</i><sup>-/-</sup>, and <i>Rev-erbβ</i><sup>-/-</sup> mice (only male mice were used in the study), along with pharmacological activation and AAV-mediated overexpression, we found that <i>Rev-erbα</i> deficiency, particularly in vascular smooth muscle cells (VSMCs), exacerbates Su5416+hypoxia (SuHx)-induced PAH, whereas REV-ERBα activation or overexpression alleviates disease. In contrast, <i>Rev-erbβ</i> loss does not affect PAH. Notably, late-stage administration of REV-ERBα agonist significantly improves established PAH. Mechanistically, REV-ERBα directly represses <i>Bnip3</i> transcription, thereby inhibiting BNIP3-driven mitophagy and improving mitochondrial function in hypoxic pulmonary artery smooth muscle cells (PASMCs). <i>Bnip3</i> knockdown phenocopies REV-ERBα activation, while <i>Bnip3</i> overexpression abrogates REV-ERBα’s anti-proliferative effects and accelerates PAH. Collectively, REV-ERBα protects against PAH by inhibiting BNIP3-driven mitophagy and preserving mitochondrial homeostasis in PASMCs. Targeting the REV-ERBα/BNIP3 axis holds promise as a circadian-based therapeutic strategy for PAH.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Targeting REV-ERBα/BNIP3 axis attenuates pulmonary arterial hypertension by repressing mitophagy in mice

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年4月2日

查看全文
  • Lejia Qiu,
  • Tingting Lu,
  • Jiayang Zhang,
  • Min Liu,
  • Hui Wang,
  • Wenyu Li,
  • Changxiao Ma,
  • Shuyao Li,
  • Baoyin Ren,
  • Qiong Wang,
  • Fenling Fan,
  • Hu Xu,
  • Feng Zheng,
  • Youfei Guan,
  • Xiaoyan Zhang,
  • Guangrui Yang,
  • Lihong Chen

摘要

Pulmonary arterial hypertension (PAH) is a life-threatening metabolic disorder. Nuclear receptors REV-ERBα and REV-ERBβ are established regulators of circadian rhythm and metabolic homeostasis, however their roles in PAH remain unclear. Using Rev-erbα+/-, VSMC-specific Rev-erbα-/-, and Rev-erbβ-/- mice (only male mice were used in the study), along with pharmacological activation and AAV-mediated overexpression, we found that Rev-erbα deficiency, particularly in vascular smooth muscle cells (VSMCs), exacerbates Su5416+hypoxia (SuHx)-induced PAH, whereas REV-ERBα activation or overexpression alleviates disease. In contrast, Rev-erbβ loss does not affect PAH. Notably, late-stage administration of REV-ERBα agonist significantly improves established PAH. Mechanistically, REV-ERBα directly represses Bnip3 transcription, thereby inhibiting BNIP3-driven mitophagy and improving mitochondrial function in hypoxic pulmonary artery smooth muscle cells (PASMCs). Bnip3 knockdown phenocopies REV-ERBα activation, while Bnip3 overexpression abrogates REV-ERBα’s anti-proliferative effects and accelerates PAH. Collectively, REV-ERBα protects against PAH by inhibiting BNIP3-driven mitophagy and preserving mitochondrial homeostasis in PASMCs. Targeting the REV-ERBα/BNIP3 axis holds promise as a circadian-based therapeutic strategy for PAH.