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Fulltext Mitochondrial Dysfunction in Diabetic Cardiomyopathy: The Possible Therapeutic Roles of Phenolic Acids

Jubaidi FF, Zainalabidin S, Mariappan V, Budin SB

Int J Mol Sci, 2020 Aug 22;21(17).
PMID: 32842567 DOI: 10.3390/ijms21176043

As the powerhouse of the cells, mitochondria play a very important role in ensuring that cells continue to function. Mitochondrial dysfunction is one of the main factors contributing to the development of cardiomyopathy in diabetes mellitus. In early development of diabetic cardiomyopathy (DCM), patients present with myocardial fibrosis, dysfunctional remodeling and diastolic dysfunction, which later develop into systolic dysfunction and eventually heart failure. Cardiac mitochondrial dysfunction has been implicated in the development and progression of DCM. Thus, it is important to develop novel therapeutics in order to prevent the progression of DCM, especially by targeting mitochondrial dysfunction. To date, a number of studies have reported the potential of phenolic acids in exerting the cardioprotective effect by combating mitochondrial dysfunction, implicating its potential to be adopted in DCM therapies. Therefore, the aim of this review is to provide a concise overview of mitochondrial dysfunction in the development of DCM and the potential role of phenolic acids in combating cardiac mitochondrial dysfunction. Such information can be used for future development of phenolic acids as means of treating DCM by alleviating the cardiac mitochondrial dysfunction.

Matched MeSH terms: Mitochondria, Heart/pathology*
Development of an In Vitro Cardiac Ischemic Model Using Primary Human Cardiomyocytes

Hafez P, Chowdhury SR, Jose S, Law JX, Ruszymah BHI, Mohd Ramzisham AR, et al.

Cardiovasc Eng Technol, 2018 09;9(3):529-538.
PMID: 29948837 DOI: 10.1007/s13239-018-0368-8

Developing experimental models to study ischemic heart disease is necessary for understanding of biological mechanisms to improve the therapeutic approaches for restoring cardiomyocytes function following injury. The aim of this study was to develop an in vitro hypoxic/re-oxygenation model of ischemia using primary human cardiomyocytes (HCM) and define subsequent cytotoxic effects. HCM were cultured in serum and glucose free medium in hypoxic condition with 1% O2 ranging from 30 min to 12 h. The optimal hypoxic exposure time was determined using Hypoxia Inducible Factor 1α (HIF-1α) as the hypoxic marker. Subsequently, the cells were moved to normoxic condition for 3, 6 and 9 h to replicate the re-oxygenation phase. Optimal period of hypoxic/re-oxygenation was determined based on 50% mitochondrial injury via 3-(4,5-dimethylthiazol-2-Yl)-2,5-diphenyltetrazolium bromide assay and cytotoxicity via lactate dehydrogenase (LDH) assay. It was found that the number of cells expressing HIF-1α increased with hypoxic time and 3 h was sufficient to stimulate the expression of this marker in all the cells. Upon re-oxygenation, mitochondrial activity reduced significantly whereas the cytotoxicity increased significantly with time. Six hours of re-oxygenation was optimal to induce reversible cell injury. The injury became irreversible after 9 h as indicated by > 60% LDH leakage compared to the control group cultured in normal condition. Under optimized hypoxic reoxygenation experimental conditions, mesenchymal stem cells formed nanotube with ischemic HCM and facilitated transfer of mitochondria suggesting the feasibility of using this as a model system to study molecular mechanisms of myocardial injury and rescue.

Matched MeSH terms: Mitochondria, Heart/pathology
Current Updates on Potential Role of Flavonoids in Hypoxia/Reoxygenation Cardiac Injury Model

Ali SS, Noordin L, Bakar RA, Zainalabidin S, Jubri Z, Wan Ahmad WAN

Cardiovasc Toxicol, 2021 08;21(8):605-618.
PMID: 34114196 DOI: 10.1007/s12012-021-09666-x

Clinically, timely reperfusion strategies to re-establish oxygenated blood flow in ischemic heart diseases seem to salvage viable myocardium effectively. Despite the remarkable improvement in cardiac function, reperfusion therapy could paradoxically trigger hypoxic cellular injury and dysfunction. Experimental laboratory models have been developed over the years to explain better the pathophysiology of cardiac ischemia-reperfusion injury, including the in vitro hypoxia-reoxygenation cardiac injury model. Furthermore, the use of nutritional myocardial conditioning techniques have been successful. The cardioprotective potential of flavonoids have been greatly linked to its anti-oxidant, anti-apoptotic and anti-inflammatory properties. While several studies have reviewed the cardioprotective properties of flavonoids, there is a scarce evidence of their function in the hypoxia-reoxygenation injury cell culture model. Hence, the aim of this review was to lay out and summarize our current understanding of flavonoids' function in mitigating hypoxia-reoxygenation cardiac injury based on evidence from the last five years. We also discussed the possible mechanisms of flavonoids in modulating the cardioprotective effects as such information would provide invaluable insight on future therapeutic application of flavonoids.

Matched MeSH terms: Mitochondria, Heart/pathology
Fulltext Ventricular pro-arrhythmic phenotype, arrhythmic substrate, ageing and mitochondrial dysfunction in peroxisome proliferator activated receptor-γ coactivator-1β deficient (Pgc-1β-/-) murine hearts

Ahmad S, Valli H, Chadda KR, Cranley J, Jeevaratnam K, Huang CL

Mech Ageing Dev, 2018 Jul;173:92-103.
PMID: 29763629 DOI: 10.1016/j.mad.2018.05.004

INTRODUCTION: Ageing and age-related bioenergetic conditions including obesity, diabetes mellitus and heart failure constitute clinical ventricular arrhythmic risk factors.
MATERIALS AND METHODS: Pro-arrhythmic properties in electrocardiographic and intracellular recordings were compared in young and aged, peroxisome proliferator-activated receptor-γ coactivator-1β knockout (Pgc-1β-/-) and wild type (WT), Langendorff-perfused murine hearts, during regular and programmed stimulation (PES), comparing results by two-way ANOVA.
RESULTS AND DISCUSSION: Young and aged Pgc-1β-/- showed higher frequencies and durations of arrhythmic episodes through wider PES coupling-interval ranges than WT. Both young and old, regularly-paced, Pgc-1β-/- hearts showed slowed maximum action potential (AP) upstrokes, (dV/dt)max (∼157 vs. 120-130 V s-1), prolonged AP latencies (by ∼20%) and shortened refractory periods (∼58 vs. 51 ms) but similar AP durations (∼50 ms at 90% recovery) compared to WT. However, Pgc-1β-/- genotype and age each influenced extrasystolic AP latencies during PES. Young and aged WT ventricles displayed distinct, but Pgc-1β-/- ventricles displayed similar dependences of AP latency upon (dV/dt)max resembling aged WT. They also independently increased myocardial fibrosis. AP wavelengths combining activation and recovery terms paralleled contrasting arrhythmic incidences in Pgc-1β-/- and WT hearts. Mitochondrial dysfunction thus causes pro-arrhythmic Pgc-1β-/- phenotypes by altering AP conduction through reducing (dV/dt)max and causing age-dependent fibrotic change.

Matched MeSH terms: Mitochondria, Heart/pathology
Fulltext Impact of prolonged nicotine administration on myocardial function and susceptibility to ischaemia-reperfusion injury in rats

Ramalingam A, Mohd Fauzi N, Budin SB, Zainalabidin S

Basic Clin Pharmacol Toxicol, 2021 Feb;128(2):322-333.
PMID: 32991780 DOI: 10.1111/bcpt.13500

This study investigated the impact of prolonged nicotine administration on myocardial susceptibility to ischaemia-reperfusion (I/R) injury in a rat model and determined whether nicotine affects mitochondrial reactive oxygen species (ROS) production and permeability transition in rat hearts. Sprague-Dawley rats were administered 0.6 or 1.2 mg/kg nicotine for 28 days, and their hearts were isolated at end-point for assessment of myocardial susceptibility to I/R injury ex vivo. Rat heart mitochondria were also isolated from a subset of rats for analysis of mitochondrial ROS production and permeability transition. Compared to the vehicle controls, rat hearts isolated from nicotine-administered rats exhibited poorer left ventricular function that worsened over the course of I/R. Coronary flow rate was also severely impaired in the nicotine groups at baseline and this worsened after I/R. Nicotine administration significantly increased mitochondrial ROS production and permeability transition relative to the vehicle controls. Interestingly, pre-incubation of isolated mitochondria with ROS scavengers (superoxide dismutase and mitoTEMPO) significantly abolished nicotine-induced increase in mitochondria permeability transition in isolated rat heart mitochondria. Overall, our data showed that prolonged nicotine administration enhances myocardial susceptibility to I/R injury in rats and this is associated with mitochondrial ROS-driven increase in mitochondrial permeability transition.

Matched MeSH terms: Mitochondria, Heart/pathology