Key result
ER stress inhibition lowers systolic blood pressure by ~39 mm Hg and reduces cardiac fibrosis.
Why the study?
Does endoplasmic reticulum stress inhibition with Tudca or PBA reduce blood pressure, cardiac remodeling, and vascular endothelial dysfunction in mice with angiotensin II-induced hypertension?
Does endoplasmic reticulum stress inhibition with Tudca or PBA reduce blood pressure, cardiac remodeling, and vascular endothelial dysfunction in mice with angiotensin II-induced hypertension?
This preclinical study demonstrates that endoplasmic reticulum stress mediates hypertension-induced cardiac fibrosis and vascular dysfunction via distinct macrovascular (TGF-β1) and microvascular (oxidative stress) pathways, identifying ER stress as a potential therapeutic target in hypertensive cardiovascular disease.
Answers are grounded in this paper and cite their sources.
ER stress inhibition merits further preclinical study in hypertension; leaves open translation to human therapy.
OBJECTIVE: Cardiac damage and vascular dysfunction are major causes of morbidity and mortality in hypertension. In the present study, we explored the beneficial therapeutic effect of endoplasmic reticulum (ER) stress inhibition on cardiac damage and vascular dysfunction in hypertension. METHODS AND RESULTS: Mice were infused with angiotensin II (400 ng/kg per minute) with or without ER stress inhibitors (taurine-conjugated ursodeoxycholic acid and 4-phenylbutyric acid) for 2 weeks. Mice infused with angiotensin II displayed an increase in blood pressure, cardiac hypertrophy and fibrosis associated with enhanced collagen I content, transforming growth factor-β1 (TGF-β1) activity, and ER stress markers, which were blunted after ER stress inhibition. Hypertension induced ER stress in aorta and mesenteric resistance arteries (MRA), enhanced TGF-β1 activity in aorta but not in MRA, and reduced endothelial NO synthase phosphorylation and endothelium-dependent relaxation (EDR) in aorta and MRA. The inhibition of ER stress significantly reduced TGF-β1 activity, enhanced endothelial NO synthase phosphorylation, and improved EDR. The inhibition of TGF-β1 pathway improved EDR in aorta but not in MRA, whereas the reduction in reactive oxygen species levels ameliorated EDR in MRA only. Infusion of tunicamycin in control mice induced ER stress in aorta and MRA, and reduced EDR by a TGF-β1-dependent mechanism in aorta and reactive oxygen species-dependent mechanism in MRA. CONCLUSIONS: ER stress inhibition reduces cardiac damage and improves vascular function in hypertension. Therefore, ER stress could be a potential target for cardiovascular diseases.
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Kassan et al. (2012) studied Angiotensin II-induced hypertension (n=100). Endoplasmic reticulum stress inhibitors (taurine-conjugated ursodeoxycholic acid [Tudca] and 4-phenylbutyric acid [PBA]) vs. Untreated angiotensin II-infused hypertensive mice and Sham control mice was evaluated on Systolic blood pressure (mm Hg) (p=<0.05). Endoplasmic reticulum stress inhibition with Tudca and PBA significantly reduced systolic blood pressure (108.4 and 111.8 vs 146.9 mm Hg; P<0.05), cardiac fibrosis, and endothelial dysfunction in hypertensive mice.
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