Gene Therapy for Mitochondrial Dysfunction in the Hearts of Diabetic Rats by Enhancing the Synthesis of Glyoxalase-1, by Methylglyoxal

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Authors: Jaipaul Singh, Sunil Rupee, Khemraj Rupee, Manal Smail, Jan Fedacko, Ram B Singh, Keshore R. Bidasee, and Fedal Alomar
Page Range: 101-105
Published in: World Heart Journal, 15#2 (2023)
ISSN: 1556-4002

Table of Contents

ABSTRACT

Background. The cardiac myocytes have three types of mitochondria, namely subsarcolemmal mitochondria (SSM), perinuclear and interfibrillar mitochondria (IFM). The SSM mitochondria are located near the plasma membrane and play a major biochemical role in ionic homeostasis and in producing energy for the heart to work efficiently as a pump. However, some disorders, such as diabetes-induced hyperglycemia, can act as an insult to cardiac mitochondria, leading to dysfunction and subsequently diabetic cardio-myopathy or heart failure over time. This study investigated the role of gene therapy to repair the dysfunctional SSM in the heart of type 1 diabetic rats. Methods. This study employed streptozotocin -induced type 1 (T1DM) diabetic rat heart compared to age-matched- control to investigate the effect of elevated blood glucose or hyperglycemia on mitochondrial function and dysfunction in the presence of pharmacological concentrations and physiological levels of the reactive carbonyl species, methylglyoxal (MGO) following gene therapy to blunt the endogenous production of MGO. Mitochondria was isolated by established biochemical methods and examined using electron microscopy for structural changes. Results. The elevated hyperglycemia can stimulate the production of the reactive carbonyl species, methylglyoxal (MGO), which is the culprit to initiate mitochondrial dysfunction via the generation established. oxygen species (ROS) and reactive carbonyl species (RCS), major oxidants in the heart. This is due to an increase in the activity of the enzyme Vaso adhesion protein 1 (VAP-1) that synthesizes MGO to pharmacological level with a concurrent decrease in the enzyme glyoxalase-I (Glo-I), which breaks down MGO. Conclusions. Gene therapy to increase the level of Glo-I to break down MGO can reverse the dysfunctional effects, resulting in normal mitochondrial function and subsequently, heart function.

Keywords: Diabetes mellitus, heart, methylglyoxal, mitochondria, gene therapy, glyoxalase-I

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