Co-administration of the flavanol (-)-epicatechin with doxycycline synergistically reduces infarct size in a model of ischemia reperfusion injury by inhibition of mitochondrial swelling

Ortiz-Vilchis, Pilar; Yamazaki, Katrina Go; Rubio-Gayosso, Iván; Ramírez-Sánchez, Israel; Calzada, Claudia; Romero-Perez, Diego; Ortiz, Alicia; Meaney, Eduardo; Taub, Pam R.; Villarreal, Francisco; Ceballos, Guillermo

doi:10.1016/j.ejphar.2014.09.042

Cited by 19 publications

(5 citation statements)

References 32 publications

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“…However, exposure to doxycycline has more intracellular effects, independent of the altered cardiac metabolism described here. As doxycycline is a calcium and iron chelator, it even has been shown to inhibit mitochondrial swelling [ 47 ]. Of note here as well is that doxycycline likely increases food intake and affects systemic inflammation [ 48 ], which could be the underlying cause of the very modest, but significantly higher body weight in the mice.…”

Section: Discussionmentioning

confidence: 99%

The Antibiotic Doxycycline Impairs Cardiac Mitochondrial and Contractile Function

Wüst

Coolen

Held

et al. 2021

IJMS

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Tetracycline antibiotics act by inhibiting bacterial protein translation. Given the bacterial ancestry of mitochondria, we tested the hypothesis that doxycycline—which belongs to the tetracycline class—reduces mitochondrial function, and results in cardiac contractile dysfunction in cultured H9C2 cardiomyoblasts, adult rat cardiomyocytes, in Drosophila and in mice. Ampicillin and carbenicillin were used as control antibiotics since these do not interfere with mitochondrial translation. In line with its specific inhibitory effect on mitochondrial translation, doxycycline caused a mitonuclear protein imbalance in doxycycline-treated H9C2 cells, reduced maximal mitochondrial respiration, particularly with complex I substrates, and mitochondria appeared fragmented. Flux measurements using stable isotope tracers showed a shift away from OXPHOS towards glycolysis after doxycycline exposure. Cardiac contractility measurements in adult cardiomyocytes and Drosophila melanogaster hearts showed an increased diastolic calcium concentration, and a higher arrhythmicity index. Systolic and diastolic dysfunction were observed after exposure to doxycycline. Mice treated with doxycycline showed mitochondrial complex I dysfunction, reduced OXPHOS capacity and impaired diastolic function. Doxycycline exacerbated diastolic dysfunction and reduced ejection fraction in a diabetes mouse model vulnerable for metabolic derangements. We therefore conclude that doxycycline impairs mitochondrial function and causes cardiac dysfunction.

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Section: Discussionmentioning

confidence: 99%

The Antibiotic Doxycycline Impairs Cardiac Mitochondrial and Contractile Function

Wüst

Coolen

Held

et al. 2021

IJMS

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“…The same dose of EPI improved heart function during in vivo persistent ischemia for 7 days in mice, along with reduced cardiac fibrosis, hypertrophy, and apoptosis, likely via activation of the PTEN/PI3K/AKT pathway [ 69 ]. A higher, 10 mg/kg dose of EPI applied alone or in combination with doxycycline in a single dose intravenously, reduced IS in rats exposed to 45 min LAD occlusion and different times of reperfusion [ 98 , 99 ]. In addition, EPI applied intragastrically in the dose 20 mg/kg/day for 21 days improved cardiac function and reduced IS in ISO-induced MI in rats, along with reduced necrosis and inflammation, likely via decreasing OxS [ 100 , 101 ].…”

Section: Effects Of Catechins On Cardiac Function Cell Viability and Infarct Size In Myocardial I/r Injurymentioning

confidence: 99%

“…It was observed in isolated mitochondria from the rat hearts undergoing the LAD coronary artery ligation leading to I/R injury and MI that EPI treatment in different concentrations (10 −8 –10 −3 M) was able to attenuate the mitochondrial swelling induced by calcium overload [ 98 ]. Previous studies of this workgroup also reported that pre-treatment with 1 mg/kg EPI in rats undergoing the LAD-induced I/R injury yields cardioprotective effects by decreasing the mitochondrial Ca 2+ overload and preserving the mitochondrial density 1 h after reperfusion [ 99 ].…”

Section: Role Of Mitochondria In Action Of Catechins In Myocardial I/r Injurymentioning

confidence: 99%

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Pharmacology of Catechins in Ischemia-Reperfusion Injury of the Heart

et al. 2021

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Catechins represent a group of polyphenols that possesses various beneficial effects in the cardiovascular system, including protective effects in cardiac ischemia-reperfusion (I/R) injury, a major pathophysiology associated with ischemic heart disease, myocardial infarction, as well as with cardioplegic arrest during heart surgery. In particular, catechin, (–)-epicatechin, and epigallocatechin gallate (EGCG) have been reported to prevent cardiac myocytes from I/R-induced cell damage and I/R-associated molecular changes, finally, resulting in improved cell viability, reduced infarct size, and improved recovery of cardiac function after ischemic insult, which has been widely documented in experimental animal studies and cardiac-derived cell lines. Cardioprotective effects of catechins in I/R injury were mediated via multiple molecular mechanisms, including inhibition of apoptosis; activation of cardioprotective pathways, such as PI3K/Akt (RISK) pathway; and inhibition of stress-associated pathways, including JNK/p38-MAPK; preserving mitochondrial function; and/or modulating autophagy. Moreover, regulatory roles of several microRNAs, including miR-145, miR-384-5p, miR-30a, miR-92a, as well as lncRNA MIAT, were documented in effects of catechins in cardiac I/R. On the other hand, the majority of results come from cell-based experiments and healthy small animals, while studies in large animals and studies including comorbidities or co-medications are rare. Human studies are lacking completely. The dosages of compounds also vary in a broad scale, thus, pharmacological aspects of catechins usage in cardiac I/R are inconclusive so far. Therefore, the aim of this focused review is to summarize the most recent knowledge on the effects of catechins in cardiac I/R injury and bring deep insight into the molecular mechanisms involved and dosage-dependency of these effects, as well as to outline potential gaps for translation of catechin-based treatments into clinical practice.

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“…In order to prevent MMP activation following AMI, some drugs such as tetracycline family have been used in previous studies [ 8 – 10 ]. Minocycline is a cheap and harmless drug of this family whose effect on cardiac remodeling has been proposed previously [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

Effect of minocycline on the left ventricular function following ST-elevation myocardial infarction treated by primary percutaneous coronary intervention

Nasiri

Shafiee

Hosseinsabet

et al. 2022

Trials

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Background Cardiac remodeling following myocardial infarction is a pathological process. We aimed to examine the effect of early short-term minocycline on the left ventricular function following ST-elevation myocardial infarction treated by the primary percutaneous coronary intervention. Methods In this double-blind, randomized controlled trial, data of 73 patients STEMI patients who were candidates for primary PCI were enrolled. Patients were then randomized to receive minocycline 50 mg orally, followed by 50 mg once a day for 5 days or a placebo with the same schedule. Measurement of serum matrix metalloproteinase-9 (MMP-9) and 2-dimensional speckle tracking echocardiography was performed at baseline and between 4 and 6 months after discharge. Then the demographic, clinical, echocardiographic, and angiographic data, as well as the levels of MMP-9, were compared between the study groups. Results There was no statistically significant difference between the study groups regarding the baseline characteristics. Serum levels of MMP-9 did not change following the intervention within each group and were not significantly different between the groups after follow-up. In the follow-up echocardiography, we also did not observe any difference between the two groups Conclusion In this study, we did not observe any effect of minocycline on cardiac remodeling based on 2-dimensional speckle tracking echocardiography and MMP-9 levels. Trial registration Iranian Registry of Clinical Trials IRCT201411188698N15. Registered on 22 June 2015, prospectively.

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Co-administration of the flavanol (-)-epicatechin with doxycycline synergistically reduces infarct size in a model of ischemia reperfusion injury by inhibition of mitochondrial swelling

Cited by 19 publications

References 32 publications

The Antibiotic Doxycycline Impairs Cardiac Mitochondrial and Contractile Function

The Antibiotic Doxycycline Impairs Cardiac Mitochondrial and Contractile Function

Pharmacology of Catechins in Ischemia-Reperfusion Injury of the Heart

Effect of minocycline on the left ventricular function following ST-elevation myocardial infarction treated by primary percutaneous coronary intervention

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