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

Apr 2, 2026Nature communications

Reducing lung blood pressure in mice by blocking a cell recycling process through the REV-ERBα/BNIP3 pathway

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Abstract

Rev-erbα deficiency in vascular smooth muscle cells significantly exacerbates Su5416+hypoxia-induced pulmonary arterial hypertension (PAH).

Activation or overexpression of REV-ERBα may alleviate PAH symptoms.
Loss of Rev-erbβ does not appear to affect the progression of PAH.
Late-stage administration of REV-ERBα agonists is associated with significant improvement in established PAH.
REV-ERBα is linked to the repression of Bnip3 transcription, which impacts mitochondrial function in pulmonary artery smooth muscle cells.
Knockdown of Bnip3 mimics the effects of REV-ERBα activation, while Bnip3 overexpression counteracts REV-ERBα's protective effects and accelerates PAH.

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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-erbβmice (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. +/--/--/-

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

Abstract

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