Estrogen deprivation aggravates cardiometabolic dysfunction in obese-insulin resistant rats through the impairment of cardiac mitochondrial dynamics

Minta, Wanitchaya; Palee, Siripong; Mantor, Duangkamol; Sutham, Wissuta; Jaiwongkam, Thidarat; Kerdphoo, Sasiwan; Pratchayasakul, Wasana; Kumfu, Sirinart; Chattipakorn, Nipon

doi:10.1016/j.exger.2018.01.006

Cited by 13 publications

(18 citation statements)

References 37 publications

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“…In addition, these three interventions also shared similar efficacy in leading to an improvement in cardiac mitochondrial function following decreased cardiac mitochondrial ROS production, mitochondrial membrane depolarization and mitochondrial swelling in ovariectomized prediabetic rats. These findings add weight to the outcome of our previous study which also found an imbalance in mitochondrial dynamics including increased mitochondrial fission in obese‐insulin resistant rats with oestrogen deprivation 55 . Consistent with these findings, we found that HFOV rats had a significantly increase in the pDrp1 at serine 616 which indicates mitochondrial fission.…”

Section: Discussionsupporting

confidence: 90%

“…Obese-insulin resistant rats with oestrogen deprivation exhibited cardiac LV dysfunction. 55 Our results found that atorvastatin, PCSK9 inhibitor and oestrogen similarly attenuated LV dysfunction.…”

Section: Discussionsupporting

confidence: 55%

“…This is consistent with our previous study which showed that 13 weeks of HFD consumption with oestrogen deprivation increased the level of mitochondrial fission proteins without any change in the level of mitochondrial fusion proteins. 55 However, the reduction in mitochondrial fusion proteins did occur in rats on a HFD for 40 weeks; therefore, it can be postulated that mitochondrial fusion protein alteration occurs after longer term HFD consumption. 44 In addition, mitochondria undergoing the fission process, concurrently with the activation of Bax, results in increased Bax activated mitochondrial release of Cyt c, which leads to caspase 3 activation and cardiomyocyte apoptosis.…”

Section: Discussionmentioning

confidence: 98%

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PCSK9 inhibitor and atorvastatin reduce cardiac impairment in ovariectomized prediabetic rats via improved mitochondrial function and Ca²⁺ regulation

Amput

Palee

Arunsak

et al. 2020

J Cellular Molecular Medi

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Post‐menopausal women have a higher risk of developing cardiometabolic dysfunction. Atorvastatin attenuates dyslipidaemia and cardiac dysfunction but it can have undesirable effects including increased risk of diabetes and myalgia. Currently, the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor efficiently reduces low‐density lipoprotein cholesterol (LDL‐C) levels more effectively than atorvastatin. We have been suggested that PCSK9 inhibitor attenuated cardiometabolic impairment more effectively than atorvastatin in ovariectomized prediabetic rats. Female Wistar rats (n = 48) were fed a normal diet (ND) or high‐fat diet (HFD) for 12 weeks. Then, HFD rats were assigned to a sham‐operated (Sham) or ovariectomized (OVX) group. Six weeks after surgery, the OVX group was subdivided into 4 treatment groups: vehicle (HFOV), atorvastatin (HFOA) (40 mg/kg/day; s.c.), PCSK9 inhibitor (HFOP) (4 mg/kg/day; s.c.) and oestrogen (HFOE 2 ) (50 µg/kg/day; s.c.) for an additional 3 weeks. Metabolic parameters, cardiac and mitochondrial function, and [Ca 2+ ] i transients were evaluated. All HFD rats became obese‐insulin resistant. HFS rats had significantly impaired left ventricular (LV) function, cardiac mitochondrial function and [Ca 2+ ] i transient dysregulation. Oestrogen deprivation (HFOV) aggravated all of these impairments. Our findings indicated that the atorvastatin, PCSK9 inhibitor and oestrogen shared similar efficacy in the attenuation in cardiometabolic impairment in ovariectomized prediabetic rats.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionsupporting

confidence: 55%

Section: Discussionmentioning

confidence: 98%

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PCSK9 inhibitor and atorvastatin reduce cardiac impairment in ovariectomized prediabetic rats via improved mitochondrial function and Ca²⁺ regulation

Amput

Palee

Arunsak

et al. 2020

J Cellular Molecular Medi

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“…Thus, by 1 month after ovariectomy, estrogen deficiency leads to an imbalance of fission and fusion, causing mitochondrial fragmentation, which has been linked to nervous system disorders (Mishra and Chan, 2014). Studies have found that estrogen deficiency can damage the mitochondrial dynamics of the heart and skeletal muscle, which can be reversed by estrogen replacement therapy (Capllonch-Amer et al, 2014;Garvin et al, 2017;Minta et al, 2018). Our study extends the literature by providing evidence that mitochondrial dysregulation triggered by estrogen deficiency contributes to cognitive impairment in AD.…”

Section: Discussionsupporting

confidence: 68%

Estrogen Deficiency Induces Mitochondrial Damage Prior to Emergence of Cognitive Deficits in a Postmenopausal Mouse Model

Zhao

Hou

Song

et al. 2021

Front. Aging Neurosci.

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Background: Estrogen deficiency contributes to the development of Alzheimer’s disease (AD) in menopausal women. In the current study, we examined the impact of estrogen deficiency on mitochondrial function and cognition using a postmenopausal mouse model.Methods: Bilateral ovariectomy was conducted in adult females C57BL/6J. Cognitive function was examined using the Morris water maze (MWM) test at 2 weeks, 1, 2, and 3 months after ovariectomy. Neurodegeneration was assessed using an immunofluorescence assay of microtubule-associated protein 2 (MAP2) in the hippocampus and immunoblotting against postsynaptic density-95 (PSD95). Mitochondrial function in the hippocampus was assessed using immunoblotting for NDUFB8, SDHB, UQCRC2, MTCO1, and ATP5A1. Mitochondrial biogenesis was examined using immunoblotting for PGC-1α, NRF1, and mtTFA. Mitochondrion fission was assessed with immunoblotting for Drp1, whereas mitochondrion fusion was analyzed with immunoblotting for OPA1 and Mfn2. Mitophagy was examined with immunoblotting for PINK1 and LC3B. Mice receiving sham surgery were used as controls.Results: Ovariectomy resulted in significant learning and memory deficits in the MWM test at 3 months, but not at any earlier time points. At 2 weeks after ovariectomy, levels of Drp1 phosphorylated at Ser637 decreased in the hippocampus. At 1 month after ovariectomy, hippocampal levels of NDUFB8, SDHB, PGC-1α, mtTFA, OPA1, and Mfn2 were significantly reduced. At 2 months after ovariectomy, hippocampal levels of MAP2, PSD95, MTCO1, NRF1, and Pink1 were also reduced. At 3 months, levels of LC3B-II were reduced.Conclusions: The cognitive decline associated with estrogen deficiency is preceded by mitochondrial dysfunction, abnormal mitochondrial biogenesis, irregular mitochondrial dynamics, and decreased mitophagy. Thus, mitochondrial damage may contribute to cognitive impairment associated with estrogen deficiency.

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“…However, cohort studies have reported that patients taking AIs—rather than tamoxifen—are more predisposed to cardiovascular diseases, including myocardial infarction and heart failure [ 12 , 13 , 14 ]. The underlying cause has been attributed to changes in lipid metabolism in the heart in response to AI-induced reduction in circulating estrogen levels [ 15 , 16 ]. This perspective seems reasonable, as estrogens play a role in energy and metabolic homeostasis [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

Letrozole Accelerates Metabolic Remodeling through Activation of Glycolysis in Cardiomyocytes: A Role beyond Hormone Regulation

Heo

Lee

et al. 2022

IJMS

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Estrogen receptor-positive (ER+) breast cancer patients are recommended hormone therapy as a primary adjuvant treatment after surgery. Aromatase inhibitors (AIs) are widely administered to ER+ breast cancer patients as estrogen blockers; however, their safety remains controversial. The use of letrozole, an AI, has been reported to cause adverse cardiovascular effects. We aimed to elucidate the effects of letrozole on the cardiovascular system. Female rats exposed to letrozole for four weeks showed metabolic changes, i.e., decreased fatty acid oxidation, increased glycolysis, and hypertrophy in the left ventricle. Although lipid oxidation yields more ATP than carbohydrate metabolism, the latter predominates in the heart under pathological conditions. Reduced lipid metabolism is attributed to reduced β-oxidation due to low circulating estrogen levels. In letrozole-treated rats, glycolysis levels were found to be increased in the heart. Furthermore, the levels of glycolytic enzymes were increased (in a high glucose medium) and the glycolytic rate was increased in vitro (H9c2 cells); the same was not true in the case of estrogen treatment. Reduced lipid metabolism and increased glycolysis can lower energy supply to the heart, resulting in predisposition to heart failure. These data suggest that a letrozole-induced cardiac metabolic remodeling, i.e., a shift from β-oxidation to glycolysis, may induce cardiac structural remodeling.

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Estrogen deprivation aggravates cardiometabolic dysfunction in obese-insulin resistant rats through the impairment of cardiac mitochondrial dynamics

Cited by 13 publications

References 37 publications

PCSK9 inhibitor and atorvastatin reduce cardiac impairment in ovariectomized prediabetic rats via improved mitochondrial function and Ca²⁺ regulation

PCSK9 inhibitor and atorvastatin reduce cardiac impairment in ovariectomized prediabetic rats via improved mitochondrial function and Ca²⁺ regulation

Estrogen Deficiency Induces Mitochondrial Damage Prior to Emergence of Cognitive Deficits in a Postmenopausal Mouse Model

Letrozole Accelerates Metabolic Remodeling through Activation of Glycolysis in Cardiomyocytes: A Role beyond Hormone Regulation

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Estrogen deprivation aggravates cardiometabolic dysfunction in obese-insulin resistant rats through the impairment of cardiac mitochondrial dynamics

Cited by 13 publications

References 37 publications

PCSK9 inhibitor and atorvastatin reduce cardiac impairment in ovariectomized prediabetic rats via improved mitochondrial function and Ca2+ regulation

PCSK9 inhibitor and atorvastatin reduce cardiac impairment in ovariectomized prediabetic rats via improved mitochondrial function and Ca2+ regulation

Estrogen Deficiency Induces Mitochondrial Damage Prior to Emergence of Cognitive Deficits in a Postmenopausal Mouse Model

Letrozole Accelerates Metabolic Remodeling through Activation of Glycolysis in Cardiomyocytes: A Role beyond Hormone Regulation

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PCSK9 inhibitor and atorvastatin reduce cardiac impairment in ovariectomized prediabetic rats via improved mitochondrial function and Ca²⁺ regulation

PCSK9 inhibitor and atorvastatin reduce cardiac impairment in ovariectomized prediabetic rats via improved mitochondrial function and Ca²⁺ regulation