Rosmarinic Acid Inhibits Platelet Aggregation and Neointimal Hyperplasia In Vivo and Vascular Smooth Muscle Cell Dedifferentiation, Proliferation, and Migration In Vitro via Activation of the Keap1-Nrf2-ARE Antioxidant System

Abstract

The activation of platelets and proliferation of vascular smooth muscle cells (VSMCs) in the vascular intima play an essential role in the pathological mechanism of vascular restenosis (RS). Rosmarinic acid (RA) is a natural phenolic acid compound. However, its mechanism of action on platelets and VSMCs is still unclear. This study investigated the effects of RA on platelet function, VSMCs phenotypic conversion, proliferation, and migration in vascular remodeling with a specific focus on the Keap1-Nrf2-ARE signaling pathway. RA inhibited platelet aggregation and Ca 2+ release and significantly reduced the release of platelet microvesicles. In addition, RA inhibited the phenotypic transition of VSMCs in vitro and in vivo. In vitro experiments showed that RA could effectively inhibit the proliferation and migration of VSMCs induced by the platelet-derived growth factor (PDGF)-BB. PDGF-BB triggered ROS generation and a decrease in mitochondrial membrane potential, which were inhibited by RA. Mechanistically, after artery injury or treatment with PDGF-BB, VSMCs presented with inhibition of the Nrf2/antioxidant response element (ARE) signaling pathway. RA treatment reversed this profile by activating the Nrf2/ARE signaling pathway; stabilizing Keap1 protein; upregulating HO-1, NQO1, GCLM, and GST protein levels; promoting typical Nrf2 nuclear translocation; and preventing VSMCs from oxidative stress damage. On the other hand, RA also inhibited the NF-κB pathway to reduce inflammation. In summary, these results indicate that RA inhibits platelet function and attenuates the proliferation, migration, and phenotypic transition of VSMCs induced by PDGF-BB in vitro and vascular remodeling in vivo. Therefore, RA treatment may be a potential therapy for preventing or treating RS.

Rosmarinic Acid Activates the Nrf2/ARE Signaling Pathway via the miR-25-3p/SIRT6 Axis to Inhibit Vascular Remodeling

“…In addition, Chen et al found that RA could attenuate the lipopolysaccharide-provoked inflammatory response of VSMCs by inhibiting the MAPK/NF-κB cascade . Our previous work demonstrated how RA affects platelet functioning and intimal neogenesis in rats with carotid balloon injury; however, the exact mechanism is largely unknown. As a result, understanding the molecular mechanism underlying the suppressive impacts of RA on vascular remodeling may aid in the design of future preventive and therapeutic measures.…”

“…A phenolic substance called rosmarinic acid is frequently found in a variety of plants from the Lamiaceae family, such as Comfreyaceae, Cucurbitaceae, Lindenaceae, and Apiaceae. , In addition to protecting vascular endothelial cells, RA has anti-inflammatory, antioxidant, and antiplatelet aggregation properties. It also has anti-inflammatory and antireperfusion-induced myocardial injury prevention properties. , Our previous study illustrated that RA inhibits platelet aggregation and intimal hyperplasia in the early stage of carotid balloon-injured rats and protects VSMCs stimulation in vitro . However, the mechanism underlying the effect of RA on neointimal hyperplasia is still unclear.…”

“…13,14 Our previous study illustrated that RA inhibits platelet aggregation and intimal hyperplasia in the early stage of carotid balloon-injured rats and protects VSMCs stimulation in vitro. 15 However, the mechanism underlying the effect of RA on neointimal hyperplasia is still unclear. microRNAs (miRNAs) are single-stranded RNA molecules that are 21−24 nucleotides long that regulate target genes posttranscriptionally by either promoting or inhibiting RNA breakdown.…”

Antiplatelet and Anticoagulant Effects of Two New Phenylpropanoid Sucrose Esters and Other Secondary Metabolites from the Aerial Part of Canna edulis

“…Eleven known compounds were isolated and identified as 6’‐acetyl‐3,6,2’‐tri‐p‐coumaroyl sucrose ( 3 ), [13] 6′‐acetyl‐3,6,2′‐triferuloyl sucrose ( 4 ), [13] tiliroside ( 5 ), [15] afzelin ( 6 ), [16] quercitrin ( 7 ), [17] 2‐hydroxycinnamaldehyde ( 8 ), [18] cinnamic acid ( 9 ), [19] 3,4‐dimethoxycinnamic acid ( 10 ), [20] dehydrovomifoliol ( 11 ), [21] 4‐hydroxy‐3,5‐dimethoxybenzaldehyde ( 12 ), [22] and (S)‐(−)‐rosmarinic acid ( 13 ) [23] by comparison of NMR data with those reported in the literature (Figure 3). Among the previously reported compounds, 3 , 4 , 6–9 , 13 have been documented for their antiplatelet aggregation and anticoagulant activities [24–28] . Cinnamic acid ( 9 ) and its derivative, 2‐hydroxycinnamaldehyde ( 8 ), also had anticancer, [29,30] and anti‐inflammatory properties [31–33] .…”

“…Among the previously reported compounds, 3, 4, 6-9, 13 have been documented for their antiplatelet aggregation and anticoagulant activities. [24][25][26][27][28] Cinnamic acid (9) and its derivative, 2-hydroxycinnamaldehyde (8), also had anticancer, [29,30] and anti-inflammatory properties. [31][32][33] Additionally, 8 was found to contribute to the restoration of liver function in cases of acetaminophen-induced acute liver injury.…”