CAFFEIC ACID AMELIORATES ANGIOTENSIN II-INDUCED INCREASE IN BLOOD PRESSURE BY ACTIVATING VASCULAR SARCO-/ENDOPLASMIC RETICULUM CA-ATPASE2A

Abstract

Objective: Many studies have focused on reporting the beneficial effect of consumption coffee or caffeine on cardiovascular disease. However, caffeic acid, a component of coffee, which has a completely different structure from caffeine, was rarely studied in cardiovascular metabolic diseases. In this study, we investigated the effect of caffeic acid on vascular function and blood pressure of mice. Design and method: Tension of endothelium-free mesenteric arteries from 8-week-old male wild-type (WT) mice was measured using wire myograph. Cytoplasmic Ca2+ and sarcoplasmic reticulum (SR) Ca2+ were measured from primary vascular smooth muscle cells (VSMCs) using fura-2AM and mag-fura-2AM, respectively. Molecular docking was performed by AutoDock to determine the binding force and sites of caffeic acid with sarco-/endoplasmic reticulum Ca-ATPase (SERCA, a channel transporting Ca2+ from the cytosol into the SR lumen. PDB: 2YFY). 8-week-old male SERCA2a knockout mice and WT littermates were surgically implanted with mini-osmotic pumps filled with angiotensin II (Ang II) solutions. Then these mice were fed with normal diet or 0.05% caffeic acids in drinking water for 8 weeks. The tail-cuff blood pressure (BP) and 24-hour ambulatory BP were measured. Results: First, we found that caffeic acid relaxed mesenteric artery pre-contracted with norepinephrine (NE) with half-effective dose of 26.7uM. Furthermore, pre-treatment with 50uM caffeic acid for 5 min completely smoothed NE-induced vasoconstriction. Specifically, we found that caffeic acid reduced intracellular Ca2+ in a concentration-dependent manner as well as resisted the increase of intracellular Ca2+ induced by thapsigargin, a SERCA inhibitor, whereas caffeic acid increased SR Ca2+ uptake. Molecular docking revealed caffeic acid binds to SERCA to form strong hydrogen bonds at ASN-359, TYR-389, ARG-604 and ASP-738. Eventually, we found that compared with the normal diet group, the intervention of caffeic acid significantly attenuated AngII-induced increases of tail BP and ambulatory BP in mice, but the hypotensive effect of caffeic acid disappeared in SERCA2a knockout mice. Conclusions: These results suggest that caffeic acid has a beneficial effect on vascular function and blood pressure by activating SERCA2a on VSMCs. Consumption coffee or caffeic acid may be an effective lifestyle to prevent and treat hypertension.