From: Paradoxical effects of statins on endothelial and cancer cells: the impact of concentrations
Statin | Dose/concentration | Cell type | Mechanism of effect | Effect on apoptosis |
---|---|---|---|---|
Fluvastatin Pravastatin | 3 µM 10–20 µM | Cardiac myocytes of Sprague–Dawley rats | Inhibition of the RhoA localization in the membrane; pravastatin did not have effect [101] | Increased |
Simvastatin Fluvastatin Pravastatin | Animal Rat fluvastatin 50Â mg/kg per day | L6 fibroblast cells and Rats in vivo | Inhibition of the RhoA localization in the membrane; pravastatin did not have effect [102] | Increased (cell line) Myotoxicity (Rat) |
Simvastatin | 71.6 µM, 143.3 µM | L6 myoblasts | Induction of tyrosine phosphorylation, 60 µM of pravastatin did not have effect on apoptosis [103] | Increased (71.6 µM), 143 µM cause necrosis |
Simvastatin | 71.6 µM | L6 myoblasts | Inhibition of the Ras isoprenylation and its downstream pathway Raf1/MEK and PI3-k [104] | Increased |
Simvastatin | Oral administration (50Â mg/kg/day) for 2Â weeks, | Animal rabbit cardiac fibers | Raised serum CK and myopathy was induced by lesions of the muscle surface membrane [105] | Increased (myopathy) |
Simvastatin, Simvastatin-acid form, and pravastatin | Simvastatin 47.8 µM, 60 µM, 71.6 µM simvastatin-acid 401 μM pravastatin μg/ml | L6 rat myoblasts | The mechanism of cell damage may relate to the [Ca2 +]i releasing and lipophilicity: Pravastatin caused little or no change in [Ca2 +]i and cell damage while simvastatin induced Apoptosis [106] | Increased by simvastatin Lipophilic statin but not pravastatin hydrophilic statin |
Fluvastatin Pitavastatin Pravastatin | 1–10 µM | Synoviocytes | Blocking geranylgeranylation of RhoA and subsequently activation of caspase 3; pravastatin had no effect [107] | Increased |
Atorvastatin Simvastatin | 100 μM | Vascular smooth muscle cells from Rat thoracic aorta | Blocking the prenylation of RhoA and downregulating the expression of Bcl-2 [78] | Increased |
Simvastatin Fluvastatin Pravastatin | 0.5–5 μM | Primary human adult cardiac myocytes | Downregulating both mRNA/protein of Mcl-1 (an inhibitor of apoptosis); pravastatin had no effect [108] | Increased |
Atorvastatin Mevast | 0.01 to 0.1 µM | HUVECs | Activate the endothelial Ras and promote Akt and mediate activation of eNOS [69] | Increased |
Atorvastatin Mevastatin |  > 0.1 µM | EPCs and Mononuclear cells | Halt angiogenesis and induce endothelial cell apoptosis [69] | Not seen even at high doses |
Atorvastatin Mevastatin | 0.1, 0.05, and 0.01 µM | EPCs and Mononuclear cells | Inhibit senescence [81] Regulation of cell cycle regulatory genes [81] | decreased |
Atorvastatin, Pravastatin Pitavastatin | nanomolar concentrations | HUVEC | Inhibit senescence via activation of Akt and then upregulation of eNOS, SIRT1, and catalase [83] | Decreased |
Simvastatin pravastatin | (0.1 µM) | In vivo: rabbit In vitro: HUVEC, COS-7 cells | Activation of Akt/eNOS and consequently induction of angiogenesis [109] |  |
Lovastatin | 2, 10, and 50 μM | In vitro Mononuclear cells (MNCs) CD34 + isolated from human umbilical cord | Lovastatin reverses the survival and function of EPCs by regulating the Akt/eNOS signaling pathway and the gene transcription of eNOS. Coincubation of 50 µM simvastatin with Triciribine induced apoptosis [110] | Inhibition of the apoptosis induced by oxLDL |
Atorvastatin Rosuvastatin | 0.01–1 μM | EPCs isolated from peripheral blood | Atorvastatin suppressed homocysteine-induced ROS accumulation and EPCs apoptosis. It also antagonized Hcy-induced activation of NADPH oxidase and overexpression of Nox4 mRNA and p-p38MAPK protein. Nox4 siRNA transfected EPCs showed a similar result [111, 112] | Decreased |
Pravastatin | 0.002, 0.02, 0.2, 2 μM | Endothelial colony-forming cells (ECFCs) | Akt- and eNOS-phosphorylation were augmented. Further, expression levels of HO-1, VEGF-A, and PlGF were increased, whereas expression levels of sFlt-1 and Eng were decreased [113] | Proliferation, migration, and tube formation of ECFCs were enhanced by pravastatin |
Atorvastatin Mevastatin | 0.1 μM 0.1 μM | EPCs | Upregulation of the telomere repeat-binding factor TRF2 [114] | Statins enhance the migratory capacity of EPCs |
Atorvastatin Mevastatin | 0.1 μM | EPCs | Atorvastatin or mevastatin dose-dependently inhibited the onset of EPC senescence in culture. Moreover, atorvastatin increased the proliferation of EPCs. Atorvastatin modulated the expression of cell cyclins while downregulating the cell cycle inhibitor, p27Kip1. The effects of statins on the senescence were independent of NO, ROS, telomerase, and Rho kinase but dependent on GGPP [115] | statins inhibited senescence of EPCs |