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Table 1 The effects of statins on apoptosis and senescence in different vascular cardiovascular cell lines

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 50 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 (50 mg/kg/day) for 2 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