Ferulic Acid Attenuates Aortic Stiffening and Cardiovascular Remodeling by Suppressing Inflammation and the Renin-Angiotensin System in Rats Fed a High-Fat/High-Carbohydrate Diet

Abstract

Background: Ferulic acid (FA) is an antioxidant compound present in cereals, fruits, and vegetables. Chronic consumption of a high-fat and high-carbohydrate (HFHC) diet can lead to metabolic syndrome and increase the risk of atherosclerotic cardiovascular disease. This study examined whether FA could mitigate vascular inflammation, aortic stiffness, and cardiovascular remodeling in rats fed a HFHC diet.

Methods: Male Sprague-Dawley rats were divided into five groups (eight rats/group): one group was fed a standard chow diet with or without FA supplementation, while the others were fed a HFHC diet plus a 15% fructose solution for 16 weeks. Rats on the HFHC diet received FA at doses of 0, 30, or 60 mg/kg/day during the final 6 weeks of the study. Various cardiovascular parameters, plasma biochemical markers, and the expression of biomarker proteins were measured.

Results: FA administration alleviated the metabolic disturbances caused by the HFHC diet. FA reduced arterial blood pressure, aortic pulse wave velocity, oxidative stress, vascular inflammation, and angiotensin-mediated myocardial fibrosis and cardiac hypertrophy, as evidenced by decreases in ventricular interstitial fibrosis and cross-sectional area. These beneficial effects were associated with reduced vascular superoxide production and lower plasma levels of angiotensin-converting enzyme and tumor necrosis factor α. FA also suppressed the expression of Ang II type 1 receptor, gp91^phox, and vascular-adhesion molecule 1 proteins and prevented hypertrophic remodeling of the aortic wall by reducing protein expression of matrix metalloproteinases 2 and 9.

Conclusion: This study provides insightful findings on the beneficial effects of FA in reducing aortic stiffness and cardiovascular remodeling associated with metabolic syndrome.

Keywords: Cardiovascular remodeling; Ferulic acid; Inflammation; Metabolic syndrome; Renin-angiotensin system; Vascular stiffness.

Figure 1

Effects of ferulic acid (FA) on systolic blood pressure (A), diastolic blood pressure (B), mean arterial blood pressure (C), pulse pressure (D), heart rate (E), and aortic pulse wave velocity (F) in all experimental groups. Values are expressed as mean±standard error of the mean (n=8/group). *P<0.05 vs. control (CON) group; ^†P<0.05 vs. high-fat and high-carbohydrate (HFHC) group; ^‡P<0.05 vs. HFHC with FA 30 mg/kg group. PG, propylene glycol.

Figure 2

Effects of ferulic acid (FA) on plasma angiotensin-converting enzyme (ACE) activity (A), vascular superoxide production (B), plasma tumor necrosis factor α (TNF-α) (C), angiotensin II type I receptor (AT₁R) protein expression (D), a transmembrane component of nicotinamide adenine dinucleotide phosphate oxidase (gp91^phox) protein expression (E), and vascular-adhesion molecule 1 (VCAM-1) protein expression (F) in all experimental groups. Values are expressed as mean±standard error of the mean (n=8/group). *P<0.05 vs. control (CON) group; ^†P<0.05 vs. highfat and high-carbohydrate (HFHC) group; ^‡P<0.05 vs. HFHC with FA 30 mg/kg group. PG, propylene glycol.

Figure 3

Effects of ferulic acid (FA) on cardiac remodeling in all experimental groups. The top panel (A) displays representative photographs of heart sections stained with hematoxylin and eosin and imaged using a stereoscope (magnification 10×) to measure left ventricular wall thickness (B), ventricular luminal area (C), and cross-sectional area (CSA) of the left ventricular wall (D). Scale bar=5 mm. Representative images of myocardial fibrosis (E) were captured using a light microscope with a 20× objective lens (scale bar=100 μm). Percentage area of myocardial fibrosis is shown in (F). Results are expressed as mean±standard error of the mean (n=6–8/group). *P<0.05 vs. control (CON) group; ^†P<0.05 vs. high-fat and high-carbohydrate (HFHC) group; ^‡P<0.05 vs. HFHC with FA 30 mg/kg group. PG, propylene glycol.

Figure 4

Effect of ferulic acid (FA) on vascular structural changes in the aortic wall of all experimental groups. Representative photomicrographs of the aortic sections (200×) stained with hematoxylin and eosin, picrosirius red, and Miller’s elastin for assessment of the cross-sectional area (CSA) of the aortic media (A), wall thickness (B), media-to-lumen (M/L) ratio (C), and area fractions of collagen (D) and elastin (E) in the aortas. Scale bar=50 μm. Results are expressed as mean±standard error of the mean (n=6–8/group). *P<0.05 vs. control (CON) group; ^†P<0.05 vs. high-fat and high-carbohydrate (HFHC) group; ^‡P<0.05 vs. HFHC with FA 30 mg/kg group. PG, propylene glycol.

Figure 5

Effect of ferulic acid (FA) on matrix metalloproteinase 2 (MMP-2) (A) and MMP-9 (B) localization in the medial layers of the aortas of all experimental groups. Scale bar=50 μm. Values are expressed as mean±standard error of the mean (n=6–8/group). *P<0.05 vs. control (CON) group; ^†P<0.05 vs. high-fat and high-carbohydrate (HFHC) group; ^‡P<0.05 vs. HFHC with FA 30 mg/kg group. PG, propylene glycol.