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Resveratrol Prevents Right Ventricle Dysfunction, Calcium Mishandling, and Energetic Failure via SIRT3 Stimulation in Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is characterized by pulmonary vessel remodeling; however, its severity and impact on survival depend on right ventricular (RV) failure. Resveratrol (RES), a polyphenol found in red wine, exhibits cardioprotective effects on RV dysfunction in PAH. However, most l...

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Autores principales: Bernal-Ramírez, Judith, Silva-Platas, Christian, Jerjes-Sánchez, Carlos, Ramos-González, Martín R., Vázquez-Garza, Eduardo, Chapoy-Villanueva, Héctor, Ramírez-Rivera, Alicia, Zarain-Herzberg, Ángel, García, Noemi, García-Rivas, Gerardo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Hindawi 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8238598/
https://www.ncbi.nlm.nih.gov/pubmed/34239697
http://dx.doi.org/10.1155/2021/9912434
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author Bernal-Ramírez, Judith
Silva-Platas, Christian
Jerjes-Sánchez, Carlos
Ramos-González, Martín R.
Vázquez-Garza, Eduardo
Chapoy-Villanueva, Héctor
Ramírez-Rivera, Alicia
Zarain-Herzberg, Ángel
García, Noemi
García-Rivas, Gerardo
author_facet Bernal-Ramírez, Judith
Silva-Platas, Christian
Jerjes-Sánchez, Carlos
Ramos-González, Martín R.
Vázquez-Garza, Eduardo
Chapoy-Villanueva, Héctor
Ramírez-Rivera, Alicia
Zarain-Herzberg, Ángel
García, Noemi
García-Rivas, Gerardo
author_sort Bernal-Ramírez, Judith
collection PubMed
description Pulmonary arterial hypertension (PAH) is characterized by pulmonary vessel remodeling; however, its severity and impact on survival depend on right ventricular (RV) failure. Resveratrol (RES), a polyphenol found in red wine, exhibits cardioprotective effects on RV dysfunction in PAH. However, most literature has focused on RES protective effect on lung vasculature; recent finding indicates that RES has a cardioprotective effect independent of pulmonary arterial pressure on RV dysfunction, although the underlying mechanism in RV has not been determined. Therefore, this study is aimed at evaluating sirtuin-3 (SIRT3) modulation by RES in RV using a monocrotaline- (MC-) induced PAH rat model. Myocyte function was evaluated by confocal microscopy as cell contractility, calcium signaling, and mitochondrial membrane potential (ΔΨm); cell energetics was assessed by high-resolution respirometry, and western blot and immunoprecipitation evaluated posttranslational modifications. PAH significantly affects mitochondrial function in RV; PAH is prone to mitochondrial permeability transition pore (mPTP) opening, thus decreasing the mitochondrial membrane potential. The compromised cellular energetics affects cardiomyocyte function by decreasing sarco-endoplasmic reticulum Ca(2+)-ATPase (SERCA) activity and delaying myofilament unbinding, disrupting cell relaxation. RES partially protects mitochondrial integrity by deacetylating cyclophilin-D, a critical component of the mPTP, increasing SIRT3 expression and activity and preventing mPTP opening. The preserved energetic capability rescues cell relaxation by maintaining SERCA activity. Avoiding Ca(2+) transient and cell contractility mismatch by preserving mitochondrial function describes, for the first time, impairment in excitation-contraction-energetics coupling in RV failure. These results highlight the importance of mitochondrial energetics and mPTP in PAH.
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spelling pubmed-82385982021-07-07 Resveratrol Prevents Right Ventricle Dysfunction, Calcium Mishandling, and Energetic Failure via SIRT3 Stimulation in Pulmonary Arterial Hypertension Bernal-Ramírez, Judith Silva-Platas, Christian Jerjes-Sánchez, Carlos Ramos-González, Martín R. Vázquez-Garza, Eduardo Chapoy-Villanueva, Héctor Ramírez-Rivera, Alicia Zarain-Herzberg, Ángel García, Noemi García-Rivas, Gerardo Oxid Med Cell Longev Research Article Pulmonary arterial hypertension (PAH) is characterized by pulmonary vessel remodeling; however, its severity and impact on survival depend on right ventricular (RV) failure. Resveratrol (RES), a polyphenol found in red wine, exhibits cardioprotective effects on RV dysfunction in PAH. However, most literature has focused on RES protective effect on lung vasculature; recent finding indicates that RES has a cardioprotective effect independent of pulmonary arterial pressure on RV dysfunction, although the underlying mechanism in RV has not been determined. Therefore, this study is aimed at evaluating sirtuin-3 (SIRT3) modulation by RES in RV using a monocrotaline- (MC-) induced PAH rat model. Myocyte function was evaluated by confocal microscopy as cell contractility, calcium signaling, and mitochondrial membrane potential (ΔΨm); cell energetics was assessed by high-resolution respirometry, and western blot and immunoprecipitation evaluated posttranslational modifications. PAH significantly affects mitochondrial function in RV; PAH is prone to mitochondrial permeability transition pore (mPTP) opening, thus decreasing the mitochondrial membrane potential. The compromised cellular energetics affects cardiomyocyte function by decreasing sarco-endoplasmic reticulum Ca(2+)-ATPase (SERCA) activity and delaying myofilament unbinding, disrupting cell relaxation. RES partially protects mitochondrial integrity by deacetylating cyclophilin-D, a critical component of the mPTP, increasing SIRT3 expression and activity and preventing mPTP opening. The preserved energetic capability rescues cell relaxation by maintaining SERCA activity. Avoiding Ca(2+) transient and cell contractility mismatch by preserving mitochondrial function describes, for the first time, impairment in excitation-contraction-energetics coupling in RV failure. These results highlight the importance of mitochondrial energetics and mPTP in PAH. Hindawi 2021-06-20 /pmc/articles/PMC8238598/ /pubmed/34239697 http://dx.doi.org/10.1155/2021/9912434 Text en Copyright © 2021 Judith Bernal-Ramírez et al. https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Bernal-Ramírez, Judith
Silva-Platas, Christian
Jerjes-Sánchez, Carlos
Ramos-González, Martín R.
Vázquez-Garza, Eduardo
Chapoy-Villanueva, Héctor
Ramírez-Rivera, Alicia
Zarain-Herzberg, Ángel
García, Noemi
García-Rivas, Gerardo
Resveratrol Prevents Right Ventricle Dysfunction, Calcium Mishandling, and Energetic Failure via SIRT3 Stimulation in Pulmonary Arterial Hypertension
title Resveratrol Prevents Right Ventricle Dysfunction, Calcium Mishandling, and Energetic Failure via SIRT3 Stimulation in Pulmonary Arterial Hypertension
title_full Resveratrol Prevents Right Ventricle Dysfunction, Calcium Mishandling, and Energetic Failure via SIRT3 Stimulation in Pulmonary Arterial Hypertension
title_fullStr Resveratrol Prevents Right Ventricle Dysfunction, Calcium Mishandling, and Energetic Failure via SIRT3 Stimulation in Pulmonary Arterial Hypertension
title_full_unstemmed Resveratrol Prevents Right Ventricle Dysfunction, Calcium Mishandling, and Energetic Failure via SIRT3 Stimulation in Pulmonary Arterial Hypertension
title_short Resveratrol Prevents Right Ventricle Dysfunction, Calcium Mishandling, and Energetic Failure via SIRT3 Stimulation in Pulmonary Arterial Hypertension
title_sort resveratrol prevents right ventricle dysfunction, calcium mishandling, and energetic failure via sirt3 stimulation in pulmonary arterial hypertension
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8238598/
https://www.ncbi.nlm.nih.gov/pubmed/34239697
http://dx.doi.org/10.1155/2021/9912434
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