Potential therapeutic effects of mTOR inhibition in atherosclerosis

Abstract

Despite significant improvement in the management of atherosclerosis, this slowly progressing disease continues to affect countless patients around the world. Recently, the mechanistic target of rapamycin (mTOR) has been identified as a pre-eminent factor in the development of atherosclerosis. mTOR is a constitutively active kinase found in two different multiprotein complexes, mTORC1 and mTORC2. Pharmacological interventions with a class of macrolide immunosuppressive drugs, called rapalogs, have shown undeniable evidence of the value of mTORC1 inhibition to prevent the development of atherosclerotic plaques in several animal models. Rapalog-eluting stents have also shown extraordinary results in humans, even though the exact mechanism for this anti-atherosclerotic effect remains elusive. Unfortunately, rapalogs are known to trigger diverse undesirable effects owing to mTORC1 resistance or mTORC2 inhibition. These adverse effects include dyslipidaemia and insulin resistance, both known triggers of atherosclerosis. Several strategies, such as combination therapy with statins and metformin, have been suggested to oppose rapalog-mediated adverse effects. Statins and metformin are known to inhibit mTORC1 indirectly via 5' adenosine monophosphate-activated protein kinase (AMPK) activation and may hold the key to exploit the full potential of mTORC1 inhibition in the treatment of atherosclerosis. Intermittent regimens and dose reduction have also been proposed to improve rapalog's mTORC1 selectivity, thereby reducing mTORC2-related side effects.

Silence of lncRNA UCA1 Represses the Growth and Tube Formation of Human Microvascular Endothelial Cells Through miR-195

“…Besides, multiple researchers have suggested that mTOR may offer new avenues in the regression of atherosclerotic plaques [36,37]. mTOR contributes in proliferation, lipogenesis, and energy metabolism possibly by targeting S6K and cyclin-dependent kinases (CDKs) [38]. Previous studies have evidenced that lncRNA UCA1 promoted malignant transformation and cancer progression through activation of mTOR pathway [14,39].…”

VAMP3 and SNAP23 mediate the disturbed flow-induced endothelial microRNA secretion and smooth muscle hyperplasia

“…mTOR is a critical regulator of many fundamental features responding to upstream cellular signals and participating in the control of gene expression and cell behavior (33). Pharmacological intervention of mTORC1 with rapamycin has shown clear evidence of the value of mTOR inhibition in preventing the development of atherosclerosis and restenosis (34,35). Although mTORC1 has been linked to endothelial function and dysfunction, its downstream targets functioning in vascular dysregulation have not been examined in detail.…”

Mechanisms of action of metformin with special reference to cardiovascular protection

“…Reduced infiltration of macrophages into the vascular wall, with reduced secretion of inflammatory cytokines, was also observed in a rabbit model of atherogenesis . The effect on angiogenesis in one of these studies and in and in other experimental studies was associated with stimulation of the AMPK/inhibition of mTOR by metformin, which suggests that such a mechanism may be of relevance to the clinical therapeutic action of metformin. Other potentially vascular protective mechanisms described for metformin in experimental studies include reduced cholesterol uptake or enhanced cholesterol efflux from macrophages, inhibition of fission of mitochondria in endothelial cells, protection of mitochondrial function during and after myocardial ischaemia, and reduced formation of foam cells or neointima in the developing plaque.…”