Liraglutide, a GLP-1 receptor agonist, inhibits vascular smooth muscle cell proliferation by enhancing AMP-activated protein kinase and cell cycle regulation, and delays atherosclerosis in ApoE deficient mice.

Several studies have demonstrated that both native glucagon-like peptide-1 (GLP-1) and GLP-1 receptor agonists suppress the progression of atherosclerosis in animal models. We investigated whether liraglutide, a GLP-1 analogue, could prevent the development of atherosclerosis in apolipoprotein E knockout mice (ApoE-/-) on a high-fat diet. We also examined the influence of liraglutide on angiotensin II-induced proliferation of rat vascular smooth muscle cells (VSMCs) via enhancement of AMP-activated protein kinase (AMPK) signaling and regulation of cell cycle progression. Treatment of ApoE-/- mice with liraglutide (400 μg/day for 4 weeks) suppressed atherosclerotic lesions and increased AMPK phosphorylation in the aortic wall. Liraglutide also improved the endothelial function of thoracic aortas harvested from ApoE-/- mice in an ex vivo study. Furthermore, liraglutide increased AMPK phosphorylation in rat VSMCs, while liraglutide-induced activation of AMPK was abolished by exendin 9-39, a GLP-1 antagonist. Moreover, angiotensin (Ang) II-induced proliferation of VSMCs was suppressed by liraglutide in a dose-dependent manner, and flow cytometry of Ang II-stimulated VSMCs showed that liraglutide reduced the percentage of cells in G2/M phase (by arrest in G0/G1 phase). These findings suggest that liraglutide may inhibit Ang II-induced VSMC proliferation by activating AMPK signaling and inducing cell cycle arrest, thus delaying the progression of atherosclerosis independently of its glucose-lowering effect.

Jojima T ，Uchida K ，Akimoto K ，Tomotsune T ，Yanagi K ，Iijima T ，Suzuki K ，Kasai K ，Aso Y ... -  《-》

Angiotensin-(1-7) regulates angiotensin II-induced matrix metalloproteinase-8 in vascular smooth muscle cells.

Angiotensin II (Ang II) is a bioactive peptide that is related to cardiovascular disease such as atherosclerosis, whereas angiotensin-(1-7) (Ang-(1-7)) is a counter-regulator of angiotensin II, which protects against cardiovascular disease. Matrix metalloproteinase 8 (MMP-8) is thought to participate in plaque destabilization though degradation of extracellular matrix, improving the development of atherosclerosis. Whether Ang-(1-7) modulates Ang II-induced MMP-8 remains unclear. In this study, we investigated the effect of Ang-(1-7) on Ang II-induced MMP-8 expression in smooth muscle cells. Smooth muscle cells were treated with Ang II, Ang-(1-7) and their antagonists. In addition, ApoE knockout mice were fed a high fat diet and subcutaneously injected with Ang II, Ang-(1-7), Ang II+Ang-(1-7) (±A779). We found that Ang II increased MMP-8 mRNA and protein expression in vascular smooth muscle cells, while Ang-(1-7) alone had no effect. However, Ang-(1-7) inhibited Ang II-induced MMP-8 expression. The inhibitory effect of Ang-(1-7) could be abolished by the competitive antagonist of Ang-(1-7) at the MAS receptor. Furthermore, Ang II induced p38 MAPK activation, and this was inhibited by the treatment of Ang-(1-7). Ang II-induced MMP-8 expression could be attenuated by the p38 MAPK inhibitor SB203580. Ang-(1-7) also significantly suppressed Ang II-induced MMP-8 in both atherosclerotic plaques and serum in ApoE-/- mice. The atherosclerotic plaques in mice treated with Ang-(1-7) and Ang II appeared to be more stable with more type I collagen contents than those in mice treated with Ang II. Our results suggest that Ang-(1-7) plays an important role in protecting against atherosclerosis via counter-regulation of Ang II-induced MMP-8.

Zhang F ，Li S ，Song J ，Liu J ，Cui Y ，Chen H ... -  《-》

Tryptanthrin Regulates Vascular Smooth Muscle Cell Phenotypic Switching in Atherosclerosis by AMP-Activated Protein Kinase/Acetyl-CoA Carboxylase Signaling Pathway.

Atherosclerosis (AS) is one of the most severe cardiovascular diseases involved in the phenotypic switching of vascular smooth muscle cells (VSMCs). Tryptanthrin is a natural product with broad biological activities. However, the effect of tryptanthrin on atherosclerotic progression is unclear. The aim of this study was to determine the role of tryptanthrin in AS and explore the potential mechanism. In vitro, primary VSMCs were stimulated with platelet-derived growth factor-BB (PDGF) to induce cell dedifferentiation. Treatment with tryptanthrin (5 μM or 10 μM) suppressed the proliferation and recovered the contractility of VSMCs in the presence of PDGF. The contractile proteins (α-smooth muscle actin, calponin, and SM22α) were increased, and the synthetic protein vimentin was decreased by tryptanthrin in PDGF-induced VSMCs. ApoE-/- mice fed with high-fat diet were used as an in vivo model of AS. Similarly, gavage administration of tryptanthrin (50 mg/kg or 100 mg/kg) attenuated VSMC phenotypic changes from a contractile to a synthetic state in aortic tissues of AS mice. The serum lipid level, atherosclerotic plaque formation, and arterial intimal hyperplasia were attenuated by tryptanthrin. Furthermore, tryptanthrin increased the expression levels of phosphorylated AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) both in vitro and in vivo. Administration of compound C, an AMPK inhibitor, reversed the inhibitory effect of tryptanthrin on VSMC dedifferentiation in vitro. Thus, we demonstrate that tryptanthrin protects against AS progression through the inhibition of VSMC switching from a contractile to a pathological synthetic phenotype by the activation of AMPK/ACC pathway. It provides novel insights into AS prevention and treatment.

Shi X ，Zhang Y ，Han J ，Peng W ，Fang Z ，Qin Y ，Xu X ，Lin J ，Xiao F ，Zhao L ，Lin Y ... -  《-》

PINK1/Parkin-mediated mitophagy promotes apelin-13-induced vascular smooth muscle cell proliferation by AMPKα and exacerbates atherosclerotic lesions.

Aberrant proliferation of vascular smooth muscle cells (VSMC) is a critical contributor to the pathogenesis of atherosclerosis (AS). Our previous studies have demonstrated that apelin-13/APJ confers a proliferative response in VSMC, however, its underlying mechanism remains elusive. In this study, we aimed to investigate the role of mitophagy in apelin-13-induced VSMC proliferation and atherosclerotic lesions in apolipoprotein E knockout (ApoE-/-) mice. Apelin-13 enhances human aortic VSMC proliferation and proliferative regulator proliferating cell nuclear antigen expression in dose and time-dependent manner, while is abolished by APJ antagonist F13A. We observe the engulfment of damage mitochondria by autophagosomes (mitophagy) of human aortic VSMC in apelin-13 stimulation. Mechanistically, apelin-13 increases p-AMPKα and promotes mitophagic activity such as the LC3I to LC3II ratio, the increase of Beclin-1 level and the decrease of p62 level. Importantly, the expressions of PINK1, Parkin, VDAC1, and Tom20 are induced by apelin-13. Conversely, blockade of APJ by F13A abolishes these stimulatory effects. Human aortic VSMC transfected with AMPKα, PINK1, or Parkin and subjected to apelin-13 impairs mitophagy and prevents proliferation. Additional, apelin-13 not only increases the expression of Drp1 but also reduces the expressions of Mfn1, Mfn2, and OPA1. Remarkably, the mitochondrial division inhibitor-1(Mdivi-1), the pharmacological inhibition of Drp1, attenuates human aortic VSMC proliferation. Treatment of ApoE-/- mice with apelin-13 accelerates atherosclerotic lesions, increases p-AMPKα and mitophagy in aortic wall in vivo. Finally, PINK1-/- mutant mice with apelin-13 attenuates atherosclerotic lesions along with defective in mitophagy. PINK1/Parkin-mediated mitophagy promotes apelin-13-evoked human aortic VSMC proliferation by activating p-AMPKα and exacerbates the progression of atherosclerotic lesions.

He L ，Zhou Q ，Huang Z ，Xu J ，Zhou H ，Lv D ，Lu L ，Huang S ，Tang M ，Zhong J ，Chen JX ，Luo X ，Li L ，Chen L ... -  《-》

Liraglutide attenuates high glucose-induced abnormal cell migration, proliferation, and apoptosis of vascular smooth muscle cells by activating the GLP-1 receptor, and inhibiting ERK1/2 and PI3K/Akt signaling pathways.

Shi L ，Ji Y ，Jiang X ，Zhou L ，Xu Y ，Li Y ，Jiang W ，Meng P ，Liu X ... -  《Cardiovascular Diabetology》