Underlying mechanism of the contractile dysfunction in atrophied ventricular myocytes from a murine model of hypothyroidism

Montalvo, Dolores; Pérez-Treviño, Perla; Madrazo-Aguirre, Katheryne; Gonzalez-Mondellini, F.A.; Miranda-Roblero, Hipólito O.; Ramonfaur-Gracia, Diego; Jacobo-Antonio, Mariana; Mayorga-Luna, Maritza; Gómez-Viquez, Norma Leticia; Garcı́a, Noemı́; Altamirano, Julio

doi:10.1016/j.ceca.2018.01.005

Cited by 19 publications

(15 citation statements)

References 89 publications

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“…Male Wistar rats (300–350 g) were used for this study. HT was induced by the administration of 6-n-propyl-2-thiouracil (PTU) (0.05%) in drinking water ad libitum for four weeks (4,5,10,22). The control group received water without PTU.…”

Section: Methodsmentioning

confidence: 99%

“…Hypothyroidism (HT) increases the risk for several cardiovascular pathologies, such as atherosclerosis, coronary disease, and the incidence of mortality due to heart failure (1,2). The cardiac muscle is one of the most thyroid hormone-responsive tissues (3,4), where key proteins controlling intracellular Ca 2+ within the myocyte are regulated, such as the sarco/endoplasmic reticulum Ca 2+ ATPase (SERCA), phospholamban (PLN), and the mitochondrial Ca 2+ uniporter (MCU) are highly regulated (5,6). These alterations diminish the intra-sarcoplasmic Ca 2+ content, impairing cell shortening (7,8).…”

Section: Introductionmentioning

confidence: 99%

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Changes in the Stoichiometry of Uniplex Decrease Mitochondrial Calcium Overload and Contribute to Tolerance of Cardiac Ischemia/Reperfusion Injury in Hypothyroidism

Chapoy‐Villanueva

Silva-Platas

Gutiérrez-Rodríguez

et al. 2019

Thyroid

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Background: Thyroid hormone status in hypothyroidism (HT) downregulates key elements in Ca2+ handling within the heart, reducing contractility, impairing the basal energetic balance, and increasing the risk of cardiovascular disease. Mitochondrial Ca2+ transport is reduced in HT, and tolerance to reperfusion damage has been documented, but the precise mechanism is not well understood. Therefore, we aimed to determine the stoichiometry and activity of the mitochondrial Ca2+ uniporter or uniplex in an HT model and the relevance to the opening of the mitochondrial permeability transition pores (mPTP) during ischemia/reperfusion (I/R) injury.Methods: An HT model was established in Wistar rats by treatment with 6-propylthiouracil for 28 days. Uniplex composition and activity were determined in cardiac mitochondria. Hearts were perfused ex vivo to induce I/R injury, and functional parameters related to contractility and tissue viability were evaluated.Results: The cardiac stoichiometry between two subunits of the uniplex (MICU1/MCU) increased by 25% in animals with HT. The intramitochondrial Ca2+ content was reduced by 40% and was less prone to the mPTP opening. After I/R injury, ischemic contracture and the onset of ventricular fibrillation were delayed in animals with HT, concomitant with a reduction in oxidative damage and mitochondrial dysfunction.Conclusions: Our results suggest that HT is associated with an increase in the cardiac MICU1/MCU ratio, thereby changing the stoichiometry between these subunits to increase the threshold to cytosolic Ca2+ and reduce mitochondrial Ca2+ overload. Our results also demonstrate that this HT model can be used to explore the role of mitochondrial Ca2+ transport in cardiac diseases due to its induced tolerance to cardiac damage.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Changes in the Stoichiometry of Uniplex Decrease Mitochondrial Calcium Overload and Contribute to Tolerance of Cardiac Ischemia/Reperfusion Injury in Hypothyroidism

Chapoy‐Villanueva

Silva-Platas

Gutiérrez-Rodríguez

et al. 2019

Thyroid

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“…All the confocal measurements were acquired using a Leica TCS SP5 confocal microscope equipped with a Dapochromatic 63x, 1.2 NA, oil objective (Leica Microsystems, Wetzlar, Germany). To assess cell volume, freshly isolated cardiomyocytes were incubated in TM with 5 μM calcein-AM (Life Technologies, Carlsbad, CA, USA) at room temperature (RT) for 30 min as previously described [17]. Then, cells were washed with a fluorophore-free and calcium-free solution and images were taken at 400 Hz, obtaining a stack of 2D images of 1 μm section thickness every 1 μm in the z -axis, covering the whole cell depth.…”

Section: Cardiomyocyte Isolationmentioning

confidence: 99%

Resveratrol Prevents Right Ventricle Remodeling and Dysfunction in Monocrotaline-Induced Pulmonary Arterial Hypertension with a Limited Improvement in the Lung Vasculature

Vázquez‐Garza

Bernal‐Ramírez

Jerjes‐Sánchez

et al. 2020

Oxidative Medicine and Cellular Longevity

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Pulmonary arterial hypertension (PAH) is a life-threatening disease that is characterized by an increase in pulmonary vascular pressure, leading to ventricular failure and high morbidity and mortality. Resveratrol, a phenolic compound and a sirtuin 1 pathway activator, has known dietary benefits and is used as a treatment for anti-inflammatory and cardiovascular diseases. Its therapeutic effects have been published in the scientific literature; however, its benefits in PAH are yet to be precisely elucidated. Using a murine model of PAH induced by monocrotaline, the macroscopic and microscopic effects of a daily oral dose of resveratrol in rats with PAH were evaluated by determining its impact on the lungs and the right and left ventricular function. While most literature has focused on smooth muscle cell mechanisms and lung pathology, our results highlight the relevance of therapy-mediated improvement of right ventricle and isolated cardiomyocyte physiology in both ventricles. Although significant differences in the pulmonary architecture were not identified either micro- or macroscopically, the effects of resveratrol on right ventricular function and remodeling were observed to be beneficial. The values for the volume, diameter, and contractility of the right ventricular cardiomyocytes returned to those of the control group, suggesting that resveratrol has a protective effect against ventricular dysfunction and pathological remodeling changes in PAH. The effect of resveratrol in the right ventricle delayed the progression of findings associated with right heart failure and had a limited positive effect on the architecture of the lungs. The use of resveratrol could be considered a future potential adjunct therapy, especially when the challenges to making a diagnosis and the current therapy limitations for PAH are taken into consideration.

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“…Thyroid hormones regulate many aspects of cardiac and vascular function, in part by controlling expression of genes regulating myocyte Ca 2+ handling and contractility (Klein and Ojamaa 2001; Gerdes and Ojamaa 2016; Jabbar et al 2017). TH deficiency as may occur in HF, was reported to reduce SR Ca 2+ and decrease the rate of SR Ca 2+ release with a blunted Ca 2+ transient amplitude (Montalvo et al 2018). A recent study showed that TH promoted functional TT development in human-induced pluripotent stem cell-derived cardiomyocytes (Parikh et al 2017).…”

Section: Introductionmentioning

confidence: 99%

Adverse transverse-tubule remodeling in a rat model of heart failure is attenuated with low-dose triiodothyronine treatment

Gilani

Huang

et al. 2019

Mol Med

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Pre-clinical animal studies have shown that triiodothyronine (T3) replacement therapy improves cardiac contractile function after myocardial infarction (MI). We hypothesized that T3 treatment could prevent adverse post-infarction cardiomyocyte remodeling by maintaining transverse-tubule (TT) structures, thus improving calcium dynamics and contractility.MethodsMyocardial infarction (MI) or sham surgeries were performed on female Sprague-Dawley rats (aged 12 wks), followed by treatment with T3 (5μg/kg/d) or vehicle in drinking water for 16 wks (n = 10–11/group). After in vivo echocardiographic and hemodynamic analyses, left ventricular myocytes were isolated by collagenase digestion and simultaneous calcium and contractile transients in single cardiomyocytes were recorded using IonOptix imaging. Live cardiomyocytes were stained with AlexaFluor-488 conjugated wheat germ agglutinin (WGA-488) or di-8-ANEPPS, and multiple z-stack images per cell were captured by confocal microscopy for analysis of TT organization. RTqPCR and immunoblot approaches determined expression of TT proteins.ResultsEchocardiography and in vivo hemodynamic measurements showed significant improvements in systolic and diastolic function in T3- vs vehicle-treated MI rats. Isolated cardiomyocyte analysis showed significant dysfunction in measurements of myocyte relengthening in MI hearts, and improvements with T3 treatment: max relengthening velocity (Vmax, um/s), 2.984 ± 1.410 vs 1.593 ± 0.325, p < 0.05 and time to Vmax (sec), 0.233 ± 0.037 vs 0.314 ± 0.019, p < 0.001; MI + T3 vs MI + Veh, respectively. Time to peak contraction was shortened by T3 treatment (0.161 ± 0.021 vs 0.197 ± 0.011 s., p < 0.01; MI + T3 vs MI + Veh, respectively). Analysis of TT periodicity of WGA- or ANEPPS-stained cardiomyocytes indicated significant TT disorganization in MI myocytes and improvement with T3 treatment (transverse-oriented tubules (TE%): 9.07 ± 0.39 sham, 6.94 ± 0.67 MI + Veh and 8.99 ± 0.38 MI + T3; sham vs MI + Veh, p < 0.001; MI + Veh vs MI + T3, p < 0.01). Quantitative RT-PCR showed that reduced expression of BIN1 (Bridging integrator-1), Jph2 (junctophilin-2), RyR2 (ryanodine receptor) and Cav1.2 (L-type calcium channel) in the failing myocardium were increased by T3 and immunoblot analysis further supporting a potential T3 effect on the TT-associated proteins, BIN1 and Jph2.In conclusion, low dose T3 treatment initiated immediately after myocardial infarction attenuated adverse TT remodeling, improved calcium dynamics and contractility, thus supporting the potential therapeutic utility of T3 treatment in heart failure.

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Underlying mechanism of the contractile dysfunction in atrophied ventricular myocytes from a murine model of hypothyroidism

Cited by 19 publications

References 89 publications

Changes in the Stoichiometry of Uniplex Decrease Mitochondrial Calcium Overload and Contribute to Tolerance of Cardiac Ischemia/Reperfusion Injury in Hypothyroidism

Changes in the Stoichiometry of Uniplex Decrease Mitochondrial Calcium Overload and Contribute to Tolerance of Cardiac Ischemia/Reperfusion Injury in Hypothyroidism

Resveratrol Prevents Right Ventricle Remodeling and Dysfunction in Monocrotaline-Induced Pulmonary Arterial Hypertension with a Limited Improvement in the Lung Vasculature

Adverse transverse-tubule remodeling in a rat model of heart failure is attenuated with low-dose triiodothyronine treatment

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