Capsaicin Improves Systemic Inflammation, Atherosclerosis, and Macrophage-Derived Foam Cells by Stimulating PPAR Gamma and TRPV1 Receptors

Abstract

Background: Capsaicin, a bioactive compound found in peppers, is recognized for its anti-inflammatory, antioxidant, and anti-lipidemic properties. This study aimed to evaluate the effects of capsaicin on atherosclerosis progression.

Methods: Apolipoprotein E knockout mice and their C57BL/6 controls were utilized to assess blood lipid profile, inflammatory status, and atherosclerotic lesions. We also examined the influence of capsaicin on cholesterol influx and efflux, and the role of TRPV1 and PPARγ signaling pathways in bone marrow-derived macrophages.

Results: Capsaicin treatment reduced weight gain, visceral adiposity, blood triglycerides, and total and non-HDL cholesterol. These improvements were associated with a reduction in atherosclerotic lesions in the aorta and carotid. Capsaicin also improved hepatic oxidative and inflammatory status. Systemic inflammation was also reduced, as indicated by reduced leukocyte rolling and adhesion on the mesenteric plexus. Capsaicin decreased foam cell formation by reducing cholesterol influx through scavenger receptor A and increasing cholesterol efflux via ATP-binding cassette transporter A1, an effect primarily linked to TRPV1 activation.

Conclusions: These findings underscore the potential of capsaicin as a promising agent for atherosclerosis prevention, highlighting its comprehensive role in modulating lipid metabolism, foam cell formation, and inflammatory responses.

Keywords: PPARγ; TRPV1; atherosclerosis; capsaicin; foam cells; inflammation.

Figure 1

Effects of capsaicin on caloric intake, body composition, glycemia, and lipid profile in WT and ApoE-Deficient mice. Calorie intake (A), weight gain (B), fat percentage (C), glycemia (D), and lipid profile (E–H) of C57BL/6 and Apo E KO animals fed cholesterol-rich diet (AIN-93M + 0.75% cholesterol) without or with 0.015% capsaicin. Bars represent the mean, and vertical lines represent the standard error. Groups not sharing the same letter = statistically different. (p < 0.05). * T Student t-test compared with group without capsaicin. N mice = WT = 5, WT + CAP = 6, ApoE − KO = 11, ApoE + Cap = 10.

Figure 2

Modulation of Inflammatory Markers by Capsaicin in WT and ApoE KO Mice. Quantification of NAG (A), MPO (B), and the cytokines TNF (C), IL-1β (D), IL-6 (E), and IL-10 (F) in the liver tissue of wild-type animals (C57BL/6) and ApoE KO mice receiving control (AIN-93M + 0.075% cholesterol) or capsaicin-containing (AIN-93M + 0.075% cholesterol + 0.015% capsaicin) diets for 5 weeks. Data are presented as mean (bars) and standard error (vertical lines). Groups not sharing the same letter = statistically different (p < 0.05). N mice = WT = 5, WT + CAP = 6, ApoE − KO = 11, ApoE + Cap = 10, except for NAG and MPO n = 5–6 mice/group.

Figure 3

Effects of Capsaicin on Atherosclerosis Development and Inflammation (A,B) Percentage of the aorta affected by atherosclerotic lesions in ApoE KO mice after five weeks of ingesting a diet rich in cholesterol with or without Cap (0.015%) n = 8–9 mice/group (C,D)—Atherosclerotic lesion area in the obstructed carotid artery n = 7 mice/group. Fluoresce intensity of monocyte/macrophage (E,F) and CD36 (G,H) staining in the carotid artery (n = 7–10 mice/group). Rolling (I,J) and adhered (K,L) cells in the mesenteric plexus blood by intravital microscopy. Data are presented as mean (bars) and standard error (vertical lines). * Statistically different (p < 0.05). Blue arrows show rolling and adhering leukocytes. N mice = 6–8 mice/group.

Figure 4

Cholesterol influx and efflux pathways in cultures treated without or with TRPV1 antagonist (CZE (A–E)) or PPARγ inhibitor (F–J). (A)—Total% of oxLDL-Dil positive populations treated or not with CZE; (B)—Total% of SRA-positive cells, treated or not with CZE; (C)—Total% of populations positive for CD36, treated or not with CZE; (D)—Total% of ABCA1-positive cells treated or not with CZE (E)—Total% of ABCG1-positive cells treated or not with CZE; (F)—Total% of oxLDL-Dil positive populations treated or not with GW9662; (G)—Total% of CD36-positive populations, treated or not with GW9662; (H)—Total% of SARS-positive cells, treated or not with GW9662; (I)—Total% of ABCA1-positive cells treated or not with GW9662; (J)—Total% of cells positive for ABCG1 treated or not with GW9662; Bars represent mean and vertical lines represent standard error (SE). Difference statistically significant (p < 0.05) is provided as (*) between each group (with or without inhibitors) and the control group (CT) without inhibitors; (—) between Caps groups treated with inhibitors and the CT group treated with inhibitors; (#) between groups treated with the inhibitor and the same group without the inhibitor.