Regulatory Effects of Statins on SIRT1 and Other Sirtuins in Cardiovascular Diseases
Abstract
:1. Introduction
2. Cholesterol, Inflammation and Cardiovascular Diseases (CVDs)
3. Sirtuins and Related Signaling Pathways
4. Evidence for Statins in the Regulation of Sirtuin-Mediated Activities
4.1. Statins Modulate Sirtuins in Inflammatory Conditions
4.2. Statins Modulates Sirtuins in CVDs
5. Conclusions and Perspectives
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Study Design | Disease | Intervention | Number of Cells | Treatment Duration | Results | Ref. | ||
---|---|---|---|---|---|---|---|---|
Case | Control | Case | Control | |||||
BMSCs of male apoE–/– | apoE–/– deficient | Atorvastatin (0 10, 100, 1000 nM) | L-DMEM containing 10% fbs. | 1 × 105 cells | 1 × 105 cells | 72 h | (1) ↑ expression of SIRT1, Runx2, ALP, and OCN (2) ↑ osteogenesis through activation of SIRT 1 | [78] |
Human THP-1 monocytic leukemia cells | Leukemia | Rosuvastatin (10 µM) | BSA/AGEs | Not mentioned | Not mentioned | 24 h | (1) AGE-RAGE → ↓ SIRT1 gene expression through ROS production (2) Inhibition of AGE-induced superoxide production → restores ↓ SIRT1 mRNA levels. | [79] |
EA.hy926 ECs | - | Atorvastatin (5 μM) Pravastatin (5 μM) | Untreated | Not mentioned | Not mentioned | 48 h | (1) ↑ SIRT1 and SIRT3 (2) ↑ fraction of SIRT1 phosphorylation by pravastatin (3) No effect on histone H3 acetylation (4) ↓ availability of nicotinamide for NAD + synthesis (possibly limiting SIRT1 activity) | [80] |
HUVEC | Senescence induced by H2O2 | Atorvastatin (50 and 100 nM), Pitavastatin (50 and 100 nM), Pravastatin (50 and 100 nM) | Vehicle (0.05% DMSO) | 1 × 105 cells | 1 × 105 cells | 24 h | (1) ↑ eNOS and SIRT1 expression (2) 100 nM of statin → protective effects against endothelial senescence | [81] |
EPCs | CAD | Atorvastatin, (0.02–0.5 μM); Rosuvastatin, (0.4–10 μM) dissolved in DMSO | vehicle | 8 × 106 cells | 8 × 106 cells | (1) ↓ miR-34a levels and ↑ SIRT1 (changes were dose dependent and were more pronounced with atorvastatin) | [82] | |
SH-SY5Y | AD | Atorvastatin (1 µM) + Aβ1–42 (2.5, 5, 10 µM) | 0.1% DMSO | Not mentioned | Not mentioned | 40 h | (1) Reverse ↓ expression of SIRT1, induced by Aβ1–42 (As neuroprotective effect) | [83] |
EA.hy926 ECs | CVD and diabetes | Rosuvastatin (1, 10 and 100 µM) | - | Not mentioned | Not mentioned | 24 h | (1) ↑ SIRT1 expression (2) No change in SIRT2 expression | [84] |
RASFs | RA | Simvastatin dissolved in ethanol (4 mg/mL) | Untreated | Not mentioned | Not mentioned | 2 h | (1) ↑ SIRT-1 and SIRT-1/FoxO3a signaling → ↓ TNF-α-induced CYR-61and phospho-FoxO3a expression | [85] |
EPCs | Atherosclerosis | Simvastatin (10, 100 nM) | - | 4000 cells | 4000 cells | 72 h | (1) ↑ TNF-α-induced ↓ SIRT1 levels → inhibition cell apoptosis | [86] |
Study Design | Disease | Intervention | Number of Animals | Treatment Duration | Results | Ref. | ||
---|---|---|---|---|---|---|---|---|
Case | Control | Case | Control | |||||
Male C57BL/6J mice | apoE–/– deficient | Atorvastatin (10 mg/kg day, i.p.) dissolved in DMSO | DMSO (equivalent amount) | n = 12 | n = 12 | 12 weeks | (1) ↑ trabecular bone volume and bone formation (2) ↑ SIRT1 expression in the bone tissue (3) Improvement in the balance of bone turnover | [78] |
Male C57BL/6J mice | HFD-induced obesity | Atorvastatin (3, 6 or 12 mg/kg/day, p.o.) | Normal diet (3.5% fat) | n = 10 | n = 10 | 7 months | (1) Activation of SIRT1 inhibition at moderate and low doses (2) High dose had no effect on SIRT1 activation. (3) Neuroprotective effect through activation of SIRT1 effect | [87] |
Male C57BL/6J mice | Ionizing radiation-induced thymus damage | Pre-administrated simvastatin (20 mg/kg/day, i.g.), 1, 3 and 7 days, following 4 Gy ⁶⁰Co γ-radiation | 0.5% CMC Na | n = 10 | n = 10 | 14 days | (1) ↑ expression of Bcl-2 and PARP and ↓ p53/p-p53 (2) ↑ expression of AKT/SIRT1 | [88] |
Male WR | HFD-induced obesity | HFD+ rosuvastatin (15 mg/kg/day) | Normal diet (3.5% fat) | n = 10 | n = 10 | 7 weeks | (1) Normalizing ↓ expression of SIRT-1, PGC-1α, PPAR-γ, and GLUT-4 | [89] |
Male C57/BL6 mice | STZ-induced diabetes | Pitavastatin (3 mg/kg /day, p.o.) | Vehicle | n = 7 | n = 7 | Lifetime of mice | (1) ↑ SIRT1 via the Akt pathway (2) Protective effect by interaction of SIRT1 with eNOS against endothelial aging (3) ↑ mitochondrial biogenesis by SIRT1-dependent manner → ↓ oxidative stress | [81] |
Male WR | Vascular aging | Atorvastatin (5 mg/kg/day) | - | n = 8 | n = 8 | 8 months | (1) ↑ SOD, NO, and eNOS expression. (2) ↑ expression of SIRT1 in ECs and VSMCs (3) SIRT1 is positively correlated with eNOS or eNOS/iNOS ratio and negatively correlated with iNOS. | [90] |
Male SD rat | CIA | Simvastatin (0.5 mg/mL, i.a.), every 5 days | Normal saline, i.a. every 5 days | n = 20 (right ankle joint of 20 rat) | n = 20 (left ankle joint of 20 rat) | 21 days | (1) ↓ CYR-61 expression → Improve arthritis | [85] |
Male SD rat | APE | Simvastatin (10 mg/kg/day, i.g.) | Untreated | n = 24 | n = 24 | 14 days | (1) ↑ mPAP, RVSP, and A-aDO2 and ↑ PaO2 (2) ↓ expression of TNF-α, IL-1β, IL-6, and IL-8 (3) ↑ mRNA expression of eNOS and SIRT2 (4) ↓ mRNA expression of NF-κB | [91] |
Male C57/BL6 mice | Type 2 diabetes | Statins (10 or 30 mg/kg/day, i.p.) in DMSO in saline | Vehicle | Not mentioned | Not mentioned | 3 days | (1) ↑ miR-495 expression → ↓ SIRT6 (2) No change in other SIRTs (3) ↑ mRNA levels of gluconeogenesis genes (4) Dysregulation of miR-495/SIRT→ FoxO1 upregulation | [92] |
Study Design | Disease | Intervention | Number of Patients | Treatment Duration | Results | Ref. | ||
---|---|---|---|---|---|---|---|---|
Case | Control | Case | Control | |||||
Retrospective study | STEMI | Simvastatin/Atorvastatin | Untreated | n = 79 | n = 91 | More than 3 years | (1) ↓ LDL (2) ↑ SIRT1 and ↓ eNOS levels (3) No changes in TOS, TAS, and OSI levels | [93] |
Retrospective study | CAD | Atorvastatin and Rosuvastatin | untreated | n = 111 (n = 91 atorvastatin, n = 20 rosuvastatin) | n = 128 | Not mentioned | (1) ↓ SIRT1 levels and ↑ eNOS levels (2) ↑ TAC, TOS levels | [3] |
Randomized controlled study | CAD | Atorvastatin (10 mg/day, n = 35) or Rosuvastatin (2.5 mg/day, n = 35) | Non-CAD group (receiving statin) | n = 70 | n = 48 | 8 months | (1) ↓ LDL-C and TAG levels (2) ↓ miR-34a and ↑ SIRT1 in the atorvastatin group and unchanged in the rosuvastatin group | [82] |
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Khayatan, D.; Razavi, S.M.; Arab, Z.N.; Khanahmadi, M.; Momtaz, S.; Butler, A.E.; Montecucco, F.; Markina, Y.V.; Abdolghaffari, A.H.; Sahebkar, A. Regulatory Effects of Statins on SIRT1 and Other Sirtuins in Cardiovascular Diseases. Life 2022, 12, 760. https://doi.org/10.3390/life12050760
Khayatan D, Razavi SM, Arab ZN, Khanahmadi M, Momtaz S, Butler AE, Montecucco F, Markina YV, Abdolghaffari AH, Sahebkar A. Regulatory Effects of Statins on SIRT1 and Other Sirtuins in Cardiovascular Diseases. Life. 2022; 12(5):760. https://doi.org/10.3390/life12050760
Chicago/Turabian StyleKhayatan, Danial, Seyed Mehrad Razavi, Zahra Najafi Arab, Maryam Khanahmadi, Saeideh Momtaz, Alexandra E. Butler, Fabrizio Montecucco, Yuliya V. Markina, Amir Hossein Abdolghaffari, and Amirhossein Sahebkar. 2022. "Regulatory Effects of Statins on SIRT1 and Other Sirtuins in Cardiovascular Diseases" Life 12, no. 5: 760. https://doi.org/10.3390/life12050760