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Figure 6 Proposed Scheme of the Mechanisms Underlying Sirolimus-Induced Vascular Dysfunction

Sirolimus (Sir) forms a complex with its receptor FK506-binding protein 12 (FKBP12), leading to cell cycle arrest by inhibition of mammalian target of sirolimus (mTOR) (10–12). Removal of FKBP12 from ryanodine receptors (RyRs) induces efflux of calcium (Ca²⁺) from the sarcoplasmic reticulum (SR), leading to protein kinase C (PKC)–mediated eNOS-Thr495 phosphorylation and consecutive reduction in NO production (14). Increased PKC activity can also induce NADPH oxidase mediated superoxide (O₂ ^–) production, in part by induction of rac1 membrane association (reviewed by Cai et al. [32]). Intracellular O₂ ^– reacts with and stimulates ATP-sensitive K⁺ channels (mitoK_ATP) in the inner mitochondrial membrane, leading to opening of the mitochondrial permeability transition pore (mPTP) and consecutive efflux of large amounts of O₂ ^– into the cytoplasm. This concept of ROS-triggered ROS formation has first been described in ischemic and angiotensin II-induced pre-conditioning [as reviewed by Brandes (38)]. The main source of mitochondrial ROS is the respiratory chain, indicated by complexes I to IV. Inhibition of K_APT channel opening as well as mPTP opening significantly decreased sirolimus-induced ROS formation. Sirolimus-induced ROS can further decrease NO bioavailability, leading to vascular dysfunction. ACh-R = acetylcholine receptor; ATP = adenosine triphosphate; c-Src = cellular homologue of the transforming gene of Rous sarcoma virus; EGFR = epidermal growth factor receptor; eNOS = endothelial nitric oxide synthase; GDP = guanosine diphosphate; GTP = guanosine triphosphate; NADPH = nicotinamide adenosine dinucleotide phosphate; NO = nitric oxide; p = phosphate-residue; Pi3K = phosphatidylinositol 3-kinase; Ptd(3,4,5)P3 = phosphatidylinositol (3,4,5)-trisphosphate; ROS = reactive oxygen species.