Table 3.
Mechanisms underlying pleiotropic and potential anti-arrhythmic effects of statins ROCK: Rho-associated coiled-coil-containing kinase; eNOS: endothelial Nitric Oxide Synthase; PI(3)K: Phosphatidylinositol-3-OH kinase; Akt: protein kinase B; mRNA: messenger ribonucleic acid; MMP: Matrix Metalloproteinase; GTPase: Guanosine Triphosphate Phosphohydrolase; NADPH: Nicotinamide Adenine Dinucleotide Phosphate Hydrogen; SMC: Smooth Muscle Cell; IL- Interleukin; TNF-α: Tumour Necrosis Factor-alpha; CRP: C-reactive protein; TGF-β: Transforming Growth Factor – beta; NF-κB: Nuclear Factor-kappa B; MAPK: Mitogen-Activated-Protein Kinase; HCM: Hypertrophic Cardiomyopathy.
| Effect | Mechanism | References |
|---|---|---|
| Improved vascular tone: | ||
| Up-regulation of endothelial nitric oxide synthase (eNOS) | Inhibition of ROCK (which downregulates eNOS) | [59,81] |
| Activation on PI(3)K/Akt pathway (which increases eNOS activity) | [68,82,83] | |
| Post-transcriptional eNOS mRNA stabilization | [67] | |
| Increase in endothelial progenitor cells | Activation on PI(3)K/Akt pathway | [84,85] |
| Inhibition of endothelin 1 | [86] | |
| Improved endothelial function | Inhibition of superoxide formation | [64] |
| Reduced plaque vulnerability | Reduction of arterial wall myocyte migration and proliferation | [87] |
| Inhibition of macrophage cholesterol esterification | [88] | |
| Inhibition of matrix metalloproteinase (e.g. MMP-2, MMP-9, MMP-12) secretion | [89,90] | |
| Anti-oxidant effects: | ||
| Inhibition of Ang II-induced superoxide formation in myocytes and vascular SMC | Inhibition of GTPase Rac1 required for NAD(P)H oxidase activity | [91] |
| Reduced mRNA expression of NADPH oxidase subunits (Nox1, p22phox) | [92] | |
| Anti-inflammatory effects | Reduced stimulation of pro-inflammatory cytokines (e.g. TNF-α, IL-1β, IL-6, IL-8, etc.) and CRP | [93] |
| Inhibition of RhoA-mediated TNF-α-induced NF-κB activation | [94] | |
| Attenuation of Ang II-mediated cardiovascular remodelling | Inhibition of Rac1-mediated NADPH oxidase activity in vascular SMCs and heart | [91] |
| Reduction of activated Ras and MAPK in a transgenic model of human HCM | [95] | |
| Inhibition of TGF-1β-Smad 2/3 signalling pathway | [96] | |