Abstract
Hypertension is a major cause of heart attack and stroke. Our recent study revealed that gallic acid (GA) exerts protective effects on pressure overload-induced cardiac hypertrophy and dysfunction. However, the role of GA in angiotensin II (Ang II)-induced hypertension and vascular remodeling remains unknown. C57BL/6J mice were subjected to saline and Ang II infusion. Systolic blood pressure was measured using a tail-cuff system. Vascular remodeling and oxidative stress were examined by histopathological staining. Vasodilatory function was evaluated in the aortic ring. Our findings revealed that GA administration significantly ameliorated Ang II-induced hypertension, vascular inflammation, and fibrosis. GA also abolished vascular endothelial dysfunction and oxidative stress in Ang II-infused aortas. Mechanistically, GA treatment attenuated Ang II-induced upregulation of the immunoproteasome catalytic subunits β2i and β5i leading to reduction of the trypsin-like and chymotrypsin-like activity of the proteasome, which suppressed degradation of endothelial nitric oxide synthase (eNOS) and reduction of nitric oxide (NO) levels. Furthermore, blocking eNOS activity by using a specific inhibitor (L-N G-nitroarginine methyl ester) markedly abolished the GA-mediated beneficial effect. This study identifies GA as a novel immunoproteasome inhibitor that may be a potential therapeutic agent for hypertension and vascular dysfunction.
Highlights
Hypertension remains a major risk factor for cardiovascular events, chronic kidney disease, and heart failure (Carey et al, 2018)
We found that angiotensin II (Ang II) infusion for 2 weeks significantly increased systolic blood pressure (SBP) compared with saline-treated controls, whereas this increase was markedly reduced by gallic acid (GA) (5 or 20 mg/kg body weight (BW)) in Ang IItreated mice (Figure 1A)
These results indicate that the administration of GA improves Ang II-induced hypertension and vascular injury
Summary
Hypertension remains a major risk factor for cardiovascular events, chronic kidney disease, and heart failure (Carey et al, 2018). Recent studies have revealed that vascular inflammation and oxidative stress, which are hallmarks of endothelial dysfunction, contribute to the pathogenesis of hypertension (Wang et al, 2016; Konukoglu and Uzun, 2017; Lang et al, 2019). Endothelial nitric oxide synthase (eNOS) acts as a key regulator of vasodilation and vasoprotection in physiological and pathological states, respectively (Garcia and Sessa, 2019). Inhibition of basal eNOS activity by administration of L-NGnitroarginine methyl ester (L-NAME) increases vasoconstriction, pathological vascular remodeling, and blood pressure (Ribeiro et al, 1992). Animal and pre-clinical studies have demonstrated that gene delivery of eNOS is effective in inhibiting vascular injury and promoting endothelial regeneration (Cooney et al, 2007). The underlying mechanisms by which the proteasome modulates eNOS stability in Ang II-induced hypertension and vascular dysfunction remain unclear
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