The Effects of Aging on Indices of Oxidative Stress and Apoptosis in the Female Fischer 344/Nnia X Brown Norway/BiNia Rat Heart

Fannin, Jacqueline; Rice, Kevin M.; Thulluri, Srininvas; Arvapalli, Ravi Kumar; Wehner, Paulette; Blough, Eric R.

doi:10.2174/1874192401307010113

Cited by 10 publications

(6 citation statements)

References 31 publications

(33 reference statements)

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“…24 Fannin et al found that increased age in the female F344xBN rat (30 months vs. 6 month) was associated with increases in markers of OS and apoptosis. 25,26 In young rats, ovariectomy has been reported to cause cardiac structural and functional that include cardiac fibrosis and hypertrophy. 27 Ovariectomized rats also exhibit OS and cardiac apoptosis.…”

Section: Discussionmentioning

confidence: 99%

The role of inflammation in driving left ventricular remodeling in a pre-HFpEF model

Loredo-Mendoza

Ramírez-Sánchez

Bustamante-Pozo

et al. 2020

Exp Biol Med (Maywood)

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We previously reported on the development of left ventricular (LV) structural and functional changes in an aged, female rat model where the effects of ovariectomy and excess weight (stimulated by fructose in water) were also explored. Ovariectomy and/or excess weight led to a prolongation of active relaxation, loss of cardiac output, and LV fibrosis in the setting of preserved ejection fraction. In this follow-up study, we wished to characterize the possible role of LV inflammation, oxidative stress (OS), and cell death in inducing such changes. Four experimental groups were studied: young (3 months old), aged (18 months old), aged + ovariectomy (OVX), and aged + ovariectomy + 10% fructose (OVF). Using conventional histology and immunohistochemistry of myocardium as well as biochemical assays of plasma samples, we document the presence of inflammatory cell aggregates in LV myocardium which are associated to high levels of plasma inflammatory cytokines (IL-1β, TNF-α, IFN-γ, TGF-β1) and OS (carbonyl proteins) in aged, OVX, and OVF vs. young animals. In the inflammatory areas, normal cardiac tissue was substituted by replacement and interstitial fibrosis and M1 macrophages, (as per by CD68 immunostaining) as we all as by co-localization with TGF-β1. We also document increases in plasma troponin I levels, loss of capillary density, cardiomyocyte hypertrophy, and death. Select changes were further aggravated by ovariectomy and/or excess weight. In conclusion, aging in the female rat heart, when compounded with estrogen depletion and excess weight promotes the development of greater levels inflammation, OS, fibrosis, capillary rarefaction, cardiomyocyte hypertrophy, and injury/death. These factors likely play an important role in the development of LV remodeling that leads to the development of a “pre-HFpEF” phenotype. Impact statement The incidence of HFpEF continues to increase and ∼2/3 of the patient population are post-menopausal women. Unfortunately, most studies focus on the use of male animal models of remodeling. In this study, however, using female rats to set a model of pre-HFpEF, we provide insights to possible mechanisms that contribute to HFpEF development in humans that will lead us to a better understanding of the underlying pathophysiology of HFpEF.

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Section: Discussionmentioning

confidence: 99%

The role of inflammation in driving left ventricular remodeling in a pre-HFpEF model

Loredo-Mendoza

Ramírez-Sánchez

Bustamante-Pozo

et al. 2020

Exp Biol Med (Maywood)

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“…Additionally, we found that the number of TUNEL-positive myonuclei, which is an apoptosis marker, was affected by aging, especially during the development and aging phases. Fannin et al [28] investigated the mitochondria-mediated apoptotic pathway in aging female F344xBN rats and suggested that aging was associated with increases in the Bax/Bcl-2 ratio, caspase-3 activation, and the number of TUNEL-positive myonuclei. Apoptosis has an important homeostatic role in normal, healthy hearts; however, excessive apoptosis leads to pathological, life-threatening heart dysfunction during the aging process [29].…”

Section: Discussionmentioning

confidence: 99%

Aging Promotes Mitochondria-Mediated Apoptosis in Rat Hearts

Choi

Cho

et al. 2020

Life

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Aging represents a major risk for developing cardiac disease, including heart failure. The gradual deterioration of cell quality control with aging leads to cell death, a phenomenon associated with mitochondrial dysfunction in the heart. Apoptosis is an important quality control process and a necessary phenomenon for maintaining homeostasis and normal function of the heart. However, the mechanism of mitochondria-mediated apoptosis in aged hearts remains poorly understood. Here, we used male Fischer 344 rats of various ages, representing very young (1 month), young (4 months), middle-aged (12 months), and old (20 months) rats, to determine whether mitochondria-mediated apoptotic signals and apoptosis in the left ventricle of the heart are altered notably with aging. As the rats aged, the extramyocyte space and myocyte cross-sectional area in their left ventricle muscle increased, while the number of myocytes decreased. Additionally, mitochondrion-mediated apoptotic signals and apoptosis increased remarkably during aging. Therefore, our results demonstrate that aging promotes remarkable morphological changes and increases the degree of mitochondrion-mediated apoptosis in the left ventricle of rat hearts.

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“…The age-related myocardial dysfunction has important implications with regard to impaired redox homeostasis (Duicu et al 2013;Judge et al 2005). Superoxide radical ions and other ROS are known to be produced as inevitable by-products of normal aerobic metabolism in cardiac tissue, while ROS may have important roles in cellular functions, such as cell signaling; furthermore, it is clear that high levels of ROS cause impaired redox homeostasis (Fanin et al 2013). There is growing evidence that increased mitochondrial ROS formation is particularly harmful for aging cells (Shinmura 2013).…”

Section: Introductionmentioning

confidence: 99%

A comprehensive study of myocardial redox homeostasis in naturally and mimetically aged rats

Cebe

Yanar

Atukeren

et al. 2014

AGE

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Age-related myocardial dysfunction has important implications with impaired redox homeostasis. Current study focused on investigation of redox homeostasis and histopathological changes in the myocardium of mimetically (MA), naturally aged (NA), and young control (YC) rats. Chronic D-galactose administration to young male Wistar rats (5 months old) was used to set up experimental aging models. We investigated 16 different oxidative damage biomarkers which have evaluated redox homeostasis of cellular macromolecules such as protein, lipid, and DNA. As a protein oxidation biomarker, advanced oxidation end products, protein carbonyl groups, protein-bound advanced glycation end products, dityrosine, kynurenine, and N-formylkynurenine concentrations in MA and NA rats were found to be significantly higher compared to those in YC rats. On the other hand, the levels of protein thiol groups were not significantly different between groups, whereas lipid peroxidation biomarkers such as conjugated diens, lipid hydroperoxides, and malondialdehyde in MA and NA rats were found to be significantly higher in comparison to those in YCs. For the assessment of oxidative DNA damage, we analyzed eight hydroxy-5'-deoxyguanosine concentrations of MA and NA groups which were higher than YCs. As an antioxidant status in the MA and NA groups, Cu-Zn superoxide dismutase, ferric reducing antioxidant power, and total thiol levels were lower than those in the YCs. Only nonprotein thiol levels were not significantly different. We also observed similar histopathological changes in MA and NA rats. We concluded that the mimetic aging model could be considered as a reliable experimental model for myocardial senescence.

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The Effects of Aging on Indices of Oxidative Stress and Apoptosis in the Female Fischer 344/Nnia X Brown Norway/BiNia Rat Heart

Cited by 10 publications

References 31 publications

The role of inflammation in driving left ventricular remodeling in a pre-HFpEF model

The role of inflammation in driving left ventricular remodeling in a pre-HFpEF model

Aging Promotes Mitochondria-Mediated Apoptosis in Rat Hearts

A comprehensive study of myocardial redox homeostasis in naturally and mimetically aged rats

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