Oral rapamycin attenuates atherosclerosis without affecting the arterial responsiveness of resistance vessels in apolipoprotein E-deficient mice

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.…”

Endothelial Dysfunction in the Apolipoprotein E-deficient Mouse: insights into the influence of diet, gender and aging

“…Studies have shown that young (6-19-week-old) male apoE -/- mice fed a standard chow diet (hypercholesterolemia only) have a preserved endothelial NO-dependent relaxation response to ACh in cutaneous vessels [101] and in the mesenteric vascular bed [102,103]. A similar phenotype has been reported in the mesenteric arteries [20,99] and skeletal muscle resistance arterioles [16,104] in adult male (20-40-week-old) mice. Interestingly, the coronary resistance vessels from this murine model fed a regular chow diet do not exhibit impaired vasodilator responses to ACh (or to PGE 2 mimetics), but they do exhibit impaired vasodilator response to bradykinin [105,106].…”

“…Other therapies have also been tested, including the systemic administration of rapamycin-eluting stents, which have been used for percutaneous coronary interventions and are associated with high eNOS and protection against atherosclerosis. Although rapamycin treatment can protect against atherosclerosis in carotid arteries [98], studies from our laboratory show that this agent does not affect vascular responsiveness in the resistance mesenteric arteries of apoE -/- mice [99]. The effect of non-pharmacological therapies on vascular dysfunction in hypercholesterolemic mice has also been tested.…”

Autophagy in Vascular Disease

“…Administration of rapalogs in mouse or rabbit models of atherosclerosis, either orally or subcutaneously, results in a marked reduction of both plaque size and plaque complexity despite severe hypercholesterolemia. [96][97][98][99][100][101][102][103][104][105] Indeed, rapalogs can prevent accumulation of macrophages and lipids and reduce cell proliferation and intraplaque angiogenesis via mTOR inhibition. 48 However, it is currently not known whether autophagy is involved in these plaque-stabilizing effects.…”