Mitochondrial Peroxiredoxin-3 protects against hyperglycemia induced myocardial damage in Diabetic cardiomyopathy
Introduction
Sedentary lifestyles have increased the occurrence of obesity, thus propelling the incidence of diabetes to reach an epidemic level. Statistical projections predict that over 300 million people will develop diabetes by 2025 [1]. Diabetic cardiomyopathy (DCM) is an independent risk factor, which impairs myocardial performance and is a key manifestation of diabetic condition [2]. Pathogenesis of DCM is multifactorial, but underlying mechanism is partially understood [3], [4], [5], [6]. Among the possible molecular mechanisms responsible for the progression of diabetic cardiomyopathy, mounting evidence from curated studies have intimately connected the generation of reactive oxygen species (ROS) and incidence of apoptosis to this state [7], [8].
Mitochondria are principle source of ROS under hyperglycemic conditions [9]. Most of the superoxide (O2∙−), produced at electron transport chain (ETC) [10], is dismutated under physiological conditions by mitochondrial Manganese superoxide dismutase (MnSOD) to form hydrogen peroxide (H2O2). Even though, MnSOD relieves mitochondrial oxidative stress caused by O2∙− [11] it further enhances a different type of oxidative stress. H2O2 can damage cellular macromolecules such as proteins, lipids, and nucleic acids, especially after its conversion to hydroxyl radical (OH∙) by Haber-Weiss reaction. Recently, our laboratory has demonstrated that Monoamine Oxidase-A (MAO-A), present in the outer mitochondrial membrane is also an important source of H2O2 and involved in development of DCM [12]. Based on these results, mitochondrial antioxidants are projected to be the first line-of-defense mechanism against ROS generation in the mitochondria and thus, may improve the myocardial performance in diabetes mellitus. Mitochondrial H2O2 can be decomposed by Glutathione peroxidases (GPxs) 1, 4 and Peroxiredoxins (Prxs) 3, 5. However, an absence of catalase in mitochondria of myocytes [13] and reduced scavenging of H2O2 by GPx1 [14] highlights the importance of Peroxiredoxins in removal of mitochondrial H2O2. Prxs are thiol-dependent antioxidants which reduce H2O2 at its cysteine residues containing active sites. Prxs are present in six isoforms Prx-1 to -6. Of these, Prx-3 contains mitochondrial localization sequence and exclusively found in mitochondria. Prx-5 is also linked with mitochondria in addition to nucleus and peroxisomes. The ability of Prx-3 and Prx-5 as active antioxidants depends on their recycling by the mitochondrial electron donor Thioredoxin-2 (Trx-2) complex [15], [16]. The reduced form of Trx-2 is then regenerated by Thioredoxin reductase-2 (TrxR2) at the expense of NADPH [17], [18], [19]. Trx-2 and TrxR2 reside in the mitochondrial matrix and operate independently from the cytosolic Trx network. According to kinetic studies, Prx-3 has emerged as a principle scavenger of H2O2 in mitochondria [20]. The greater efficiency of mitochondrial Prx-3 and -5 together with Trx-2, TrxR2 and NADPH, may attribute to protection against high glucose induced oxidative stress. Infact, overexpression of Prx-3 has been reported to prevent the left ventricular remodeling after myocardial infarction in transgenic mice [21], and Prx-3 also has crucial role in contractile function of skeletal muscle by regulating mitochondrial homeostasis [22]. Prx-5 overexpression protects mitochondrial DNA damage induced by H2O2 [23] and also human tendon cells against apoptosis and loss of cellular function during oxidative stress [24]. However, the role of mitochondrial Prx in DCM prevention has not been explored to its full potential.
In the current study, we found that Prx-3 but not Prx-5 expression was significantly reduced in the heart of diabetic rats. Therefore, the aim of present study was to examine the effect of Prx-3 induction on oxidative stress induced myocardial damage in diabetic condition.
Section snippets
In vivo animal model
Male Wistar rats were bred and maintained at animal house facility of National Centre for Cell Science. All animal experiments were duly approved by the Institutional Animal Ethics Committee (IAEC) under reference number IAEC/2012/B-195 dated on 8/9/12 of National Centre for Cell Science and were performed in full compliance of the extant guidelines and principles. Food and water were available ad libitum. Diabetes was induced at 6–8 weeks of age by single intraperitoneal (IP) injection of
Prx-3 expression is down regulated in cardiac cells under hyperglycemic condition
Excessive oxidative stress, induced by ROS and RNS generation is associated with diabetic cardiomyopathy [31]. To determine whether mitochondrial antioxidants Prx-3, Prx-5 and their electron donor Trx-2 are involved in the regulation of hyperglycemia induced oxidative stress, we examined their expression levels in both in vitro and in vivo models. H9c2 cells, at 60% confluency, were subjected to normal and high glucose for 24, 48, 72 and 96 h. Expression of Prx-3 and Trx-2 were found to be
Discussion
The current study demonstrates that overexpression of the mitochondrial antioxidant; Prx-3, offers enhanced protection against diabetes-induced cardiac injury. We observed that Prx-3 induction by quercetin treatment prevented a multitude of cardiac complications such as contractility defects, hypertrophy, myocardial fibrosis and apoptosis in STZ induced diabetic rats. Under in vitro conditions too, beneficial effects of Prx-3 gene overexpression were found to be associated with an attenuation
Authors’ contributions
S.A. and S.L.S. contributed to the design of the study, data analysis, and interpretation of results. S.A., P.U., S.S., contributed to data acquisition. S.A., P.U., S.S., and S.L.S. contributed to drafting of the manuscript.
Conflicts of interests
The authors declare that they have no conflicts of interest associated with this manuscript.
Sources of funding
This work was supported by intramural funding of National Centre for Cell Science, Department of Biotechnology, India. SA (Sr. No. 2061030780) PU (Sr. No. 2061030917) and SS (Sr. No. 2061030712) and are recipients of University Grants Commission (UGC) Senior Research Fellowship.
Acknowledgments
We thank Dr. S.C. Mande, Director, National Centre for Cell Science (Pune, India) for encouragement and support. We express thanks to Aparajita Dasgupta for proofreading the manuscript. We also acknowledge help from the staff of the experimental animal facility at the National Centre for Cell Science.
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Contributed equally to this work.