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.

Keywords: atherosclerosis; mTOR; metformin; rapalogs; rapamycin.

Figure 1

Schematic representation of the protein complexes mTORC1 and mTORC2. Whereas both complexes feature mTOR, Deptor and mLST8, mTORC1 engages with Raptor, Rheb‐GTP and Pras40 while mTORC2 is associated with Rictor, Protor‐1 and mSin1. Accordingly, both complexes control distinct cellular functions. Rapalogs are able directly to inhibit mTORC1 and, when given chronically, can also disrupt mTORC2 signalling. Other drugs, such as metformin, inhibit mTORC1 via indirect means, such as activation of REDD1 and AMPK, while inhibiting RAG‐GTPase. AMPK, 5' adenosine monophosphate‐activated protein kinase α; mLST8, mammalian lethal with SEC13 protein 8; mTOR, mechanistic target of rapamycin; mTORC, mechanistic target of rapamycin complex; mSin1, mammalian stress‐activated protein kinase‐interacting protein 1; REDD1, regulated in development and DNA damage responses 1; ATP, adenine triphosphate; RAG, ras‐related GTPase; Rheb, ras homolog enriched in brain; Pras40, proline‐rich AKT substrate of 40 kDa; Raptor, regulatory associated protein of mTOR; Deptor, DEP domain containing mTOR‐interacting protein; CDK's, cyclin dependent kinases; 4eBP‐1, eukaryotic initiation factor 4E binding protein 1; Srebp1, sterol regulatory element‐binding protein 1; HIF‐1a, Hypoxia‐inducible factor 1a; VEGF, vascular endothelial growth factor; S6K1, p70 ribosomal protein S6 kinase 1; IRS‐1, insulin receptor substrate 1; AKT, protein kinase B; Protor‐1, protein observed with Rictor 1; Rictor, rapamycin insensitive companion of mTOR; PKCa, protein kinase C a; SGK1, serum and glucocorticoid‐induced protein kinase 1

Figure 2

Chemical structure of sirolimus (or semi‐derivatives thereof) and tacrolimus. (A) Different functional groups can be added to sirolimus, resulting in several semi‐derivatives with improved pharmacokinetics. (B) Unlike sirolimus, tacrolimus has no polyene mTOR‐binding region. Thus, while both drugs form complexes with FKBP12, tacrolimus lacks the ability to influence mTOR signalling. mTOR, mechanistic target of rapamycin

Figure 3

Inhibition of mTORC1 in atherosclerosis. Inhibitors of mTORC1 counteract atherosclerosis on several levels by reducing: (1) chemokine levels; (2) monocyte adhesion and migration; (3) monocyte/macrophage proliferation; (4) endothelial dysfunction; (5) foam cell formation; (6) macrophage inflammatory responses; (7) hypoxia‐inducible factor‐1α (HIF 1α) production; and (8) intraplaque angiogenesis. IL, interleukin; MMP, matrix metalloproteinase; mTORC, mechanistic target of rapamycin complex; TNF‐ α, tumour necrosis factor α