Potential therapeutic effects of mTOR inhibition in atherosclerosis

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 preeminent actor 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 inhibit 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 due 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 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

Jaar van publicatie:2016

Trefwoorden:A1 Journal article

BOF-keylabel:ja

BOF-publication weight:1

CSS-citation score:4

Authors from:Higher Education

Toegankelijkheid:Open