Anti-atherosclerotic effects of sirolimus on human vascular smooth muscle cells

Abstract

Ma KL, Ruan XZ, Powis SH, Moorhead JF, Varghese Z. Antiatherosclerotic effects of sirolimus on human vascular smooth muscle cells. Am J Physiol Heart Circ Physiol 292: H2721-H2728, 2007. First published February 23, 2007 doi:10.1152/ajpheart.01174.2006.-Sirolimus is a potent immunosuppressive agent and has an anti-atherosclerotic effect through its anti-proliferative property. The present study was undertaken to investigate the effect of sirolimus on intracellular cholesterol homeostasis in human vascular smooth muscle cells (VSMCs) in the presence of inflammatory cytokine IL-1␤. We explored the effect of sirolimus on the lipid accumulation of VSMCs in the presence of IL-1␤, using Oil Red O staining and quantitative measurement of intracellular cholesterol. The effect of sirolimus on the gene and protein expression of lipoprotein receptors and ATP binding cassettes (ABCA1 and ABCG1) was examined by real-time PCR and Western blotting, respectively. Furthermore, the effect of sirolimus on cholesterol efflux from VSMCs in the presence or absence of IL-1␤ was also investigated using [ 3 H] cholesterol efflux. Finally, we examined the effect of sirolimus on the production of inflammatory cytokines in VSMCs using ELISA. Sirolimus reduced intracellular lipid accumulation in VSMCs mediated by IL-1␤ possibly due to the reduction of expression of low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL) receptors. Sirolimus increased cholesterol efflux from VSMCs and overrode the suppression of cholesterol efflux induced by IL-1␤. Sirolimus also increased ABCA1 and ABCG1 genes expression, even in the presence of IL-1␤. We further confirmed that sirolimus inhibited mRNA and protein expression of inflammatory cytokines IL-6, tumor necrosis factor-␣, IL-8, and monocyte chemoattractant protein-1. Inhibition of lipid uptake together with increasing cholesterol efflux and the inhibition of inflammatory cytokines are all important aspects of the anti-atherosclerotic effects of sirolimus on VSMCs. cholesterol homeostasis; foam cell; inflammatory cytokine ATHEROSCLEROSIS is a multifactorial disease; disordered lipid metabolism and chronic inflammation are important contributory factors (16,32). Vascular smooth muscle cells (VSMCs) play a key role during the pathogenesis of vascular lesion, although they are not always the main cell component of atherosclerotic lesions, especially in the early stages. In normal vessels, the majority of VSMCs reside in the media, where they are quiescent and possess a "contractile" phenotype characterized by the abundance of actin-and myosin-containing filaments (4, 33). In disease states, VSMCs reenter the cell cycle, proliferate, and migrate from media to intima (33). After vessel injury, intimal VSMCs have a synthetic phenotype, characterized by hyperplasia or hypertrophy and matrix protein accumulation in the intima and/or media with or without lipid deposition, resulting in thickening and stiffness of the arterial wall. Foam cells have traditionally been regarded as being derived f...

Downstream coronary effects of drug-eluting stents

“…[16][17][18] However, several studies also suggest that cell-cycle inhibitors may possess antiatherogenic properties. [19][20][21][22][23] Although published data are conflicted, it appears that overall outcomes, including target vessel revascularization rates, are slightly more favorable in patients receiving DES, although this has to be weighed against higher stent costs and the necessity for prolonged, uninterrupted antiplatelet therapy. 24,25 In addition, there are differences in the rates of target vessel versus target lesion revascularization rates, implying that pathologic processes are modified in other regions of the stented coronary.…”

“…16,17 Multiple studies have demonstrated the atherosclerotic attenuation of sirolimus in Apolipoprotein E-deficient mice and human vascular smooth muscle cells. [19][20][21][22] A variety of studies investigating coronary artery disease in heart transplant patients, who have baseline endothelial dysfunction, have shown that antiproliferatives such as sirolimus attenuate the rate of atherosclerotic progression. 29,30 In addition, paclitaxel is a well-known immunomodulatory agent and has also been associated with atherosclerotic regression in animal models, as well as reduced inflammation in stented porcine arteries.…”

Synthesis of three-arm block copolymer poly(lactic-<em>co</em>-glycolic acid)&ndash;poly(ethylene glycol) with oxalyl chloride and its application in hydrophobic drug delivery

“…Apart from the cumulative percentage of RPM, as shown in Figure 6B, the RPM amount released per day gradually reduced, but there was always drug detected in the release solution, which can still play an inhibitory role in cell proliferation. 55 Drug can be released from the delivery system in a sustained manner to prolong exposure time and increase the drug-therapy efficacy. 56,57 Physically entrapped drugs were released mainly through the diffusion effect, so the driving force was reducing with the concentration of drugs in the core decreasing gradually.…”

Everolimus Triggers Cytokine Release by Macrophages

“…7 Second, everolimus has significant antimacrophage activity that is mediated by at least 2 potentially independent mechanisms, namely the inhibition of monocyte chemotaxis 8 and the induction of macrophage death by autophagy. 9,10 Third, everolimus prevents lipid accumulation in macrophages and SMCs due to inhibition of endogenous cholesterol synthesis, 11 downregulation of low-density lipoprotein (LDL) receptors and scavenger receptors, 12,13 as well as upregulation of cholesterol efflux genes. 12,13 Other beneficial effects include upregulation of endothelial nitric oxide synthase (eNOS) in low shear regions, which are susceptible to atherosclerosis, 14 and inhibition of hyaluronan deposition by SMCs, 15 a product that stimulates monocyte adhesion to the extracellular matrix.…”