Inositol Requiring Enzyme 1α Mediates Hypertension and Vascular Remodeling

BACKGROUND: Chronic unfolded protein response due to endoplasmic reticulum stress has been proposed as a therapeutic target for hypertension. Here, we tested our hypothesis that inactivation of one of the central unfolded protein response effectors, inositol-requiring enzyme 1α, mitigates hypertension and vascular remodeling in mice infused with angiotensin II. METHODS: C57BL6 mice were infused with angiotensin II for 2 weeks with or without an inositol-requiring enzyme 1α inhibitor KIRA6 treatment to evaluate blood pressure and cardiovascular remodeling. Mouse small mesenteric arteries were used to assess vascular reactivity. Rat vascular smooth muscle cells were used to assess inositol-requiring enzyme 1α activation, intracellular Ca 2+ concentration, and secretory phenotype via proteomics. RESULTS: KIRA6 treatment mitigated hypertension induced by angiotensin II infusion. KIRA6 treatment also prevented angiotensin II–induced vascular thickening and perivascular fibrosis. Immunohistochemical staining of aortas indicated that phosphorylated inositol-requiring enzyme 1α signal in vascular smooth muscle cells was elevated with angiotensin II infusion and attenuated with KIRA6 treatment. Vasoconstriction in small mesenteric arteries after incubation with angiotensin II was attenuated by KIRA6 coincubation. Angiotensin II–induced elevation in intracellular Ca 2+ concentration was partially reduced by KIRA6 pretreatment in vascular smooth muscle cells. Proteomic analysis demonstrated that angiotensin II induced a unique secretory phenotype in vascular smooth muscle cells, which was mitigated by KIRA6. CONCLUSIONS: Targeting inositol-requiring enzyme 1α is a potential therapy for hypertension and vascular remodeling by reducing vascular resistance, mitigating intracellular Ca 2+ elevation, and protecting against secretory phenotype in vascular smooth muscle cells.