Leptin-enhanced neointimal hyperplasia is reduced by mTOR and PI3K inhibitors

Abstract

Despite the use of the sirolimus (rapamycin) drug-eluting coronary stent, diabetics are at increased risk of developing in-stent restenosis for unclear reasons. Hyperleptinemia, which often coexists with diabetes and metabolic syndrome, is an independent risk factor for progression of coronary artery disease. It has not been determined whether elevated circulating leptin decreases the efficacy of the sirolimus drug-eluting stent in inhibiting neointimal hyperplasia, the process underlying restenosis after stenting. Here we show that leptin activates the mammalian target of rapamycin (mTOR) signaling pathway in primary murine vascular smooth muscle cells (VSMC) and stimulates VSMC proliferation in a PI3K-dependent fashion. Exogenous leptin, administered at levels comparable to those found in obese humans, promotes neointimal VSMC hyperplasia in a murine femoral artery wire injury model. Leptin significantly increases the dose of the mTOR inhibitor sirolimus that is required for effective inhibition of neointimal formation. Combination therapy with LY294002, a PI3K inhibitor, and sirolimus effectively inhibits leptin-enhanced neointimal hyperplasia. These data show that, in the setting of hyperleptinemia, higher doses of an mTOR inhibitor, or combination therapy with mTOR and PI3K inhibitors, inhibits neointimal hyperplasia after arterial injury. These studies may explain the higher rates of restenosis observed in diabetics treated with a sirolimus-eluting coronary stent and suggest a potential novel therapeutic approach for inhibiting in-stent restenosis in such patients. metabolic syndrome ͉ vascular disease ͉ neointimal formation ͉ vascular smooth muscle cells

Mammalian Target of Rapamycin (mTOR) Induces Proliferation and De-Differentiation Responses to Three Coordinate Pathophysiologic Stimuli (Mechanical Strain, Hypoxia, and Extracellular Matrix Remodeling) in Rat Bladder Smooth Muscle

“…1 regulator of proliferation and de-differentiation. 17,35,36 Vascular smooth muscle cells proliferation following mechanical strain during arterial distension by balloon angioplasty was inhibited with rapamycin, similar to our mechanical strain responses in BSMCs. 37 Two main families of mTOR-dependant signaling kinases are responsible for mRNA translation 38 : the S6 kinases (S6Ks) and the eukaryotic initiation factor 4E (EIF4E)-binding proteins, which mediate 5Ј-terminal oligopolylpyrimidine (5Ј-TOP) mRNA translation and 5Ј-cap-dependent mRNA translation, respectively.…”

Neuroendocrine regulation of autophagy by leptin

“…Besides, the activity of mTOR complex 1 is elevated in muscles from ob/ob mice. 28 In sharp contrast to the aforementioned results, recombinant leptin inhibits AMPK and consequently provokes the activation of mTOR in some cell types, for instance in hypothalamic neurons, 16 primary vascular smooth muscle cells, 29 hepatic stellate cells, 30 as well as peritoneal macrophages, 31,32 suggesting that leptin can inhibit autophagy as well. Accordingly, insulinproducing β cells from pancreatic islet exhibit increased autophagy in db/db mice.…”

Autophagy in cardiovascular biology

“…Rapamycin induces VSMC differentiation by specific activation of the Akt2 isoform, promoting expression of contractile proteins (129). In fact, arachidonic acid, TGF-β, FK506, and leptin induce VSMC proliferation through PI3K-dependent activation of mTOR (130)(131)(132)(133). Thus, autophagy in VSMCs can confer both adaptive and maladaptive actions depending on the context.…”