Carnosine Impedes PDGF-Stimulated Proliferation and Migration of Vascular Smooth Muscle Cells In Vitro and Sprout Outgrowth Ex Vivo

Abstract

Carnosine, a naturally producing dipeptide, exhibits various beneficial effects. However, the possible role of carnosine in vascular disorders associated with pathological conditions, including proliferation and migration of vascular smooth muscle cells (VSMCs), largely remains unrevealed. Here, we investigated the regulatory role and mechanism of carnosine in platelet-derived growth factor (PDGF)-induced VSMCs. Carnosine inhibited the proliferation of PDGF-induced VSMCs without any cytotoxic effects. Carnosine treatment also induced G1-phase cell cycle arrest by causing a p21WAF1-mediated reduction in the expression of both cyclin-dependent kinases (CDKs) and cyclins in PDGF-treated VSMCs. Carnosine treatment suppressed c-Jun N-terminal kinase (JNK) phosphorylation in PDGF-stimulated signaling. Additionally, carnosine significantly prevented the migration of VSMCs exposed to PDGF. Carnosine abolished matrix metalloproteinase (MMP)-9 activity via reduced transcriptional binding activity of NF-κB, Sp-1, and AP-1 motifs in PDGF-treated VSMCs. Moreover, using aortic assay ex vivo, it was observed that carnosine addition attenuated PDGF-stimulated sprout outgrowth of VSMCs. Taken together, these results demonstrated that carnosine impeded the proliferation and migration of PDGF-stimulated VSMCs by regulating cell cycle machinery, JNK signaling, and transcription factor-mediated MMP-9 activity as well as prevented ex vivo sprout outgrowth of blood vessels. Thus, carnosine may be a potential candidate for preventing vascular proliferative disease.

Liensinine Prevents Vascular Inflammation by Attenuating Inflammatory Mediators and Modulating VSMC Function

“…At a 30 µg/mL concentration of liensinine, the proliferation of VSMC was almost completely inhibited to the level of the control (without PDGF) (Figure 3). The potent anti-proliferative activity of liensinine at a concentration of 30 µg/mL is comparable to 50 µM of epigallocatechin-3-O-gallate [47] and 20mM of carnosine [48]. Likewise, liensinine at a concentration of 10, 20 and 30 µg/mL significantly attenuated the expression of MMP-9 induced by TNF-α (Figure 4).…”

Effect of Secretome-Hypoxia Mesenchymal Stem Cells on Regulating SOD and MMP-1 mRNA Expressions in Skin Hyperpigmentation Rats

“…TGF-βs bind to two serine/ threonine kinase receptors consisting of TGF-βRI and TGF-βRII [40]. When the ligand binds, TGF-βRII phosphorylates TGF-βRI and activates intracellular signaling pathways such as Smad3, MAPK, including cellular signaling-associated protein kinase (ERK1/2), p38 MAPK, and c-Jun N-terminal kinase [16], [41]. In skin fibroblasts, p38 MAPK and Smad3 unite in regulating TGF-β-induced MMP-13 expression, whereas ERK1/2 cooperates with Smad3 in controlling connective tissue growth factor expression [38], [42], [43].…”