Different Approaches in Therapy Aiming to Stabilize an Unstable Atherosclerotic Plaque
Abstract
:1. Introduction
2. General Considerations
3. Approaches Directed at Specific Molecular Pathways
3.1. Approach towards Regulation of Metabolism
3.2. Approach towards Macrophages and Cellular Death Mechanisms
3.3. Approach toward Inflammation and Immune Reactions
3.4. Approach towards Reactive Oxygen Species—Antioxidation Therapy
3.5. Approach towards Extracellular Matrix Remodeling and Neovascularization
3.6. Specific Approaches—Summary
4. An Integrated Approach
5. Clinical Studies Conforming Plaque Stabilization
6. Alternative Approaches
7. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Approaches | Examples and Mechanisms | Investigated Drugs * |
---|---|---|
Metabolic approach | LDL lowering therapy: |
|
Recombinant HDL particles [28] | 75 mg/kg of apoA-I(Milano) | |
Iron depletion → increased iron mobilization from macrophages [88,89] | Iron chelation therapy (deferasirox) | |
MGL depletion → 2‑AG ↑, CB2R activation [90] | N/A (genetic knock-out organisms used in this experiment) | |
Cell survival promotion approach |
| |
| ||
STAT6 upregulation → M2 macrophage polarization [92] | N/A (overexpression by recombinant pcDNA) | |
Prevention from excessive PARP1 activation by severe DNA damage → prevention from ATP depletion [93] | For example, 3-Aminobenzamide (3-AB), doxycycline, thieno(2,3-c)isoquinolin-5-one (TIQ-A) | |
Anti-inflammatory approach |
| |
|
| |
Cytotoxic CD8 + T lymphocyte (Tc) depletion [100] | CD8α or CD8β targeted monoclonal antibody | |
Regulatory T lymphocyte (Treg) promotion [101]. | For example, IL-2, mycophenolate mofetil, vitamin D, rapamycin, G-CSF | |
Reactive oxygen species approaches | Downregulation of ROS generators (e.g., NADPH oxidases NOX2) [71] | Nox2 inhibitor peptide (a chimeric 18-amino acid peptide) |
Attenuation of ROS derivative (e.g., 7β‑OH) activity [60]. | N/A (indirect methods like conjugation by glutathione) | |
Promotion of ROS scavengers (such as HO-1 induced by Nrf transcriptional factor) [102] | N/A | |
Direct ROS abruption (e.g., polyphenols) [103] | Different polyphenols (in this study–apple polyphenols) | |
ECM remodeling and neovascularization approach | Inhibition of matrix metalloproteinase (MMPs) synthesis and activity (especially MMP9) [104] | Ghrelin |
Promotion of collagen synthesis (e.g., by melatonin through Akt phosphorylation and subsequent P4Hα1 upregulation) [105] | Dietary nitrate treatment (KNO3 or KNO2) | |
Influence on fibronectin (e.g., blockade of fibronectin-integrin α5 pathway) [106] | In vivo knockdown of phosphodiesterase 4D5 (siRNA) | |
Inhibition of neovascularization (e.g., through bFGF blockade) [107] | K5 (a small molecule bFGF-inhibitor) |
STUDY NAME | Treatment | No. of Investigated Patients (Period) | Clinical Outcome (MACE, Mortality) | Plaque Stabilization Effect (IVUS or OCT) |
---|---|---|---|---|
GAIN [133] 1 | Atorvastatin (20–80 mg) vs. placebo | 65 and 66 (12 months) | Any ischemic event: 21.5% vs. 31.8% (p = 0.184) | IVUS: Larger hyperechogenicity index 42.2% vs. 10.1%, p = 0.021 |
REVERSAL [134] 2 | Atorvastatin 80 mg (intensive lipid-lowering) vs. Pravastatin 40 mg(moderate lipid-lowering) | 253 and 249 (18 months) | Death: 0.3% vs. 0.3%—NS Myocardial infarction: 1.2% vs. 2.1%—NS | IVUS: Lower percent atheroma volume change 0.2% vs. 1.6%, p < 0.001 |
PRECISE-IVUS [37] 3 | Atorvastatin * + ezetimibe (10 mg) vs. Atorvastatin * alone | 102 and 100 (9–12 months) | Cardiovascular events ** 11% vs. 14%—NS | IVUS: Change in normalized TAV −6.6% vs. −1.4%, p < 0.001 |
GLAGOV [135] 4 | Statin *** + PCSK9i (evolocumab 420 mg monthly) vs. Statin *** alone | 423 and 423 (19 months) | Death: 0.6% vs. 0.8%—NS Non-fatal myocardial infarction: 2.1% vs 2.9%—NS | IVUS: Change in TAV −5.8% vs. –0.9%, p < 0.001 |
Christoph et al. [136] | Pioglitazone (30 mg) vs. Placebo | 27 and 27 (9 months) | Insignificant differences, no MACE registered | VH-IVUS: Decrease in the necrotic core −1.3% vs. + 2.6%, p = 0.008 |
Tondapu et al. [137] | Rosuvastatin (10 mg) vs. Atorvastatin (20 mg) | 24 and 19 (12 months) | Not applicable | OCT: Increased FCT **** 171.5 vs. 127.0 μm, p = 0.03; Decreased macrophages |
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Kowara, M.; Cudnoch-Jedrzejewska, A. Different Approaches in Therapy Aiming to Stabilize an Unstable Atherosclerotic Plaque. Int. J. Mol. Sci. 2021, 22, 4354. https://doi.org/10.3390/ijms22094354
Kowara M, Cudnoch-Jedrzejewska A. Different Approaches in Therapy Aiming to Stabilize an Unstable Atherosclerotic Plaque. International Journal of Molecular Sciences. 2021; 22(9):4354. https://doi.org/10.3390/ijms22094354
Chicago/Turabian StyleKowara, Michal, and Agnieszka Cudnoch-Jedrzejewska. 2021. "Different Approaches in Therapy Aiming to Stabilize an Unstable Atherosclerotic Plaque" International Journal of Molecular Sciences 22, no. 9: 4354. https://doi.org/10.3390/ijms22094354