TABLE 1.
Summary of recent therapies based on targeting mitochondria in I/R.
| Mitochondrial target | Pharmacological agent/therapy | Study design | Mechanism of action/effect | References |
|---|---|---|---|---|
| mPTP opening: CypD | CsA | In vivo in male Sprague-Dawley rats | Reduces infarct size and IRI | Xie and Yu (2007) |
| Porcine model of I/R | No reduction in infarct size | Karlsson et al. (2010), Karlsson et al. (2012) | ||
| Randomized controlled trial | Positive effects when administered at reperfusion during acute myocardial infarction | Piot et al. (2008) | ||
| Clinical trials: NCT01502774 | Fails to cardioprotect, no improvement in clinical outcomes of STEMI patients | Cung et al. (2015) | ||
| NCT01650662 | Ottani et al. (2016) | |||
| Randomized controlled trial | Ghaffari et al. (2013) | |||
| mPTP opening: CypD | SS31 | In vitro on isolated mitochondria and in vivo in male Dorsett hybrid sheep and male New Zealand White rabbits, ex vivo in guinea pig I/R models | Targets the IMM, binds to cardiolipin and reduces ROS | Zhao et al. (2004), Kloner et al. (2012) |
| Clinical trial with STEMI patients (EMBRACE STEMI) | No reduction in myocardial infarct size | Gibson et al. (2016) | ||
| mPTP opening: CypD | CsA@PLGA-PEG-SS31 | In vitro in H9c2 | Decreases cell death by inhibiting mPTP activity and apoptotic cascade activation | Zhang et al. (2019a) |
| In vivo in male Sprague–Dawley rats I/R models | Reduces myocardial infarction | |||
| mPTP opening: CypD | Combination of CsA and Pitavastatin nanoparticles | In vivo in male C57BL/6J mice I/R models | Targets mPTP and inflammation, reduces the infarct size | Ikeda et al. (2021) |
| mPTP opening: CypD | Sanglifehrin A (SfA) | In vivo in female Sprague-Dawley rats | Cardioprotection only in early reperfusion time | Parodi-Rullan et al. (2018) |
| mPTP opening: CypD | C31 | In vitro in H9c2, adult mouse cardiomyocytes and isolated mouse cardiac mitochondria | Inhibited CypD peptidylprolyl cis-trans isomerase (PPIase) activity and mitochondrial swelling | Panel et al. (2021) |
| Ex vivo in male C57BL/6J mice I/R models | No effect after systemic administration | |||
| mPTP opening | AP39 | In vitro in H9c2 and isolated cardiac mitochondria, in vivo in male Wistar rats and C57BL/6J mice I/R models | Inhibits mPTP and reduces infarct size | Karwi et al. (2017), Chatzianastasiou et al. (2016) |
| mPTP opening: Oxidative stress | Lycopene (LP) | In vitro in H9c2, ex vivo in male Wistar rats I/R models | Blocking mPTP activity and the mitochondrial apoptotic cascade through the modulation of Bax and Bcl-2 | Li et al. (2019b) |
| mPTP opening: Oxidative stress | SS31-peptide-resveratrol | In vitro in H9c2, in vivo in I/R rats | Reduces of mitochondrial ROS, inhibits mPTP opening, and decreases apoptosis, reduces infarct size | Cheng et al. (2019) |
| mPTP opening: c subunit of ATP synthase | 1,3,8-triazaspiro [4.5]decane (PP11) | In vitro in HeLa, ex vivo in Wistar rats I/R models | Decreases the apoptotic cell death | Morciano et al. (2018) |
| Improves cardiac function after I/R | ||||
| Succinate oxidation | Chloramphenicol succinate (CAPS) | In vivo in porcine heart | Reduces IRI and increases autophagy | Sala-Mercado et al. (2010) |
| Oxidative stress | MitoSNO | In vivo in C57BL/6J mice I/R model | Reduction in ROS production, oxidative damage and IRI. | Chouchani et al. (2013), Prime et al. (2009) |
| In vitro in H9c2 | ||||
| Oxidative stress | Amobarbital | Ex vivo in male Fisher rats, mice and rabbits I/R model | Protects mitochondria against ROS overproduction and ischemic damage, blocks of electron transport, decreases mPTP opening, protects against apoptosis during I/R | Chen et al. (2006), Chen and Lesnefsky (2011), Xu et al. (2013) |
| Oxidative stress | S1QELs | In vitro in H9c2 and ex vivo in male C57BL/6J mice I/R models | Destroy superoxide-H2O2 production at complex I and their correlated damage | Brand et al. (2016) |
| Oxidative stress | KAI-9803 (δPKC inhibitor peptide) | In vivo porcine model of acute myocardial infarction | Decreases apoptosis and necrosis | Inagaki et al. (2003) |
| Clinical trial with Acute Myocardial Infarction patients (DELTA MI) | Shows an acceptable safety and tolerability profile but no reduction of biomarkers of IRI | Bates et al. (2008) | ||
| Clinical trial NCT00785954 | Lincoff et al. (2014) | |||
| Oxidative stress | MitoQ | In vivo in male Wistar rat I/R models | Accumulates in the mitochondrial matrix, decreases oxidative injury, ameliorates cardiac function reducing tissue damage | Adlam et al. (2005) |
| Mouse model of heterotopic heart transplantation | Reduces graft damage via oxidative stress inhibition | Dare et al. (2015) | ||
| Oxidative stress | N-[(R)-1,2-dithiolane-3-pentanoyl]-L-glutamyl-l-alanine (CMX-2043) | In vivo in male Sprague-Dawley rat I/R models | Decreases infarct damage both before and during the ischemic injury and at reperfusion | Baguisi et al. (2016) |
| Mitochondrial biogenesis: PPARs | Bezafibrate | Randomized controlled trial (BIP) | Reduces major cardiac events and mortality | Madrid-Miller et al. (2010), Goldenberg et al. (2008), Goldenberg et al. (2009) |
| Mitochondrial biogenesis: PPARs | Thiazolidinediones (TZDs), Pioglitazone | Randomized controlled trial | Decreases cardiovascular deaths, non-fatal myocardial infarction | Liu and Wang (2017) |
| Mitochondrial biogenesis: PPARs | Rosiglitazone | In vivo in swine models and male rat model | Fails to prevent the ΔΨm collapse, nor reduces the mitochondrial ROS. No positive effect on cardiac function | Palee et al. (2011) |
| Meta-analysis on clinical trials | Associated to potential serious adverse cardiovascular effects | Nissen and Wolski (2007) | ||
| Mitochondrial biogenesis: AMPK agonist | 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) | In vitro in neonatal rat cardiac myocytes | Protects against ischemic insult | Sunaga et al. (2019) |
| Mitochondrial biogenesis: AMPK agonist | Metformin | In vitro in human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and in mitochondria isolated from human cardiac tissue | A biphasic impact: at low concentration, increases OCR and mitochondrial biogenesis; at high concentration, increases glycolysis, attenuates superoxide production and inhibits Ca2+-induced mPTP opening | Emelyanova et al. (2021) |
| Murine cardiac acute and chronic transplantation models | Reduces cardiac rejection and limit acute IRI | Chin et al. (2011) | ||
| In vivo in male Wistar rat I/R models | Improves cardiac function following the reduction of mitochondrial fission, ROS production, apoptosis, and mitochondrial swelling | Palee et al. (2020) | ||
| Randomized controlled trials | Contradictory results | Holman et al. (2008), Mellbin et al. (2008), Hartman et al. (2017) | ||
| mPTP opening | Melatonin | In vitro in neonatal cardiac microvascular endothelial cells, in vivo in Sprague–Dawley rat I/R models | Inhibits mPTP opening, inhibits autophagy via AMPK/mTOR signaling. Reduces cardiac damage | Chen et al. (2018) |
| Oxidative stress | ||||
| Mitochondrial fusion | M1 | In vivo in male Wistar rat I/R models, in vitro in embryonic fibroblasts (MEFs) | Decreases infarct size and cardiac apoptosis | Maneechote et al. (2019) |
| Mitophagy | Rapamycin | In vivo in male Wistar rat I/R models, in vitro in H9c2 | Promotes autophagy, reduces cardiomyocyte apoptosis and infarct size after I/R | Gao et al. (2020) |
| Mitophagy: Inhibition of mTORC1 | Everolimus | In vivo in male Wistar rat I/R models | Prevents left ventricular remodeling after myocardial infarction | Buss et al. (2009) |
| Mitochondrial fission: Drp1 | Mdivi-1 | In vitro in murine neonatal cardiomyocytes, ex vivo in male Sprague-Dawley rat I/R models | Preserves OCR and cardiomyocytes function, improves diastolic function | Sharp et al. (2014) |
| In vitro in HL-1 and adult murine cardiomyocytes, in vivo C57BL/6 male mice I/R models | Decreases mPTP sensitivity and reduces cell death after I/R, reduces infarct size | Ong et al. (2010) | ||
| In vivo C57BL/6 male diabetic mice I/R models | Reduces the troponin I levels, lactate dehydrogenase activity, blocks mPTP opening, attenuates cardiac injury | Ding et al. (2017) | ||
| In vitro in HL-1 | Pre-ischemic treatment shows cardioprotection, treatment during reoxygenation upregulates to necroptosis | Dong et al. (2016) | ||
| In vivo swine model of myocardial infarction | Treatment at the onset of reperfusion do not reduce infarct size nor ameliorate cardiac function | Ong et al. (2019) | ||
| Mitochondrial fission: Drp1 | Drpitor1 and Drpitor1a | Ex vivo in male Sprague-Dawley rat I/R models | Decreases ROS production and preserves diastolic function | Wu et al. (2020) |
| Mitochondrial fission: Drp1 | P110 | In vitro rat primary cardiomyocytes, ex vivo rat I/R model, and in vivo in male Wistar rat I/R models | Improves mitochondrial O2 consumption and cardiac function, reduces autophagy and apoptosis | Disatnik et al. (2013) |
| Mitochondrial fission: Drp1 | Hydralazine | In vitro in mouse embryonic fibroblasts and ventricular cardiomyocites. In vivo and ex vivo in C57/BL6 mouse I/R model | Reduces cardiomyocyte death and infarct size | Kalkhoran et al. (2022) |
| Mitochondrial fission: Drp1 | miR-499 | In vitro in neonatal rat cardiomyocytes and in vivo in rat and mice I/R model | Inhibits apoptotic pathway and ameliorates cardiac function | Wang et al. (2011) |
| Autophagy | EPO | In vitro in rat ventricular cardiomyocytes In vivo in male Sprague-Dawley rat I/R models | Reduces sensitivity of mPTP to ROS, reduces infarct size attenuating ventricular damage | Ahmet et al. (2011) |
| In vitro in H9c2 | Increases cell viability, decreases autophagy through activation of PI3K/Akt pathway | Lin et al. (2020) | ||
| Mitochondrial functionality | Mitochondria transplantation | In vitro in neonatal rat cardiomyocytes In vivo in New Zealand White rabbit I/R models | Reduces markers of myocardial injury and infarct size, reduces inflammatory markers and necrosis | Masuzawa et al. (2013) |
| Ex vivo in New Zealand White rabbit I/R models | Perfusion through the coronary vasculature leads to reduction of infarct size and enhanced post-ischemic myocardial function | Cowan et al. (2016) | ||
| Pediatric patients who required central extracorporeal membrane oxygenation support for I/R associated myocardial dysfunction after cardiac surgical procedure | No short-term adverse reactions, improves ventricular function | Emani et al. (2017) | ||
| Pediatric patients who required central extracorporeal membrane oxygenation support for cardiogenic shock due to IRI after cardiac surgery | No arrhytmias, no inflammatory or immune response, enhances ventricular strain | Guariento et al. (2021) | ||
| In vitro in H9c2 In vivo in male Sprague-Dawley rat I/R models | Reduces inflammation and oxidative stress and protects mitochondrial integrity, ameliorates cardiac function | Lee et al. (2018) | ||
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Metformin Confers Cardiac and Renal Protection in Sudden Cardiac Arrest via AMPK Activation. Cody A. Rutledge, Claudia Lagranha, Takuto Chiba, Kevin Redding, Donna B. Stolz, Sunder Sims-Lucas, Cameron Dezfulian, Jonathan Elmer, Brett A. Kaufman bioRxiv 2021.08.24.457506; doi: https://doi.org/10.1101/2021.08.24.457506).