Resveratrol Prevents Right Ventricle Dysfunction, Calcium Mishandling, and Energetic Failure via SIRT3 Stimulation in Pulmonary Arterial Hypertension. (21st June 2021)

• Record Type: Journal Article
• Authors: 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
• Other Names: Santulli Gaetano Academic Editor.
• Is Part Of: Oxidative medicine and cellular longevity. Volume 2021(2021)
• Publication Date: 2021-06-21
• Subjects: Oxidative stress -- Periodicals; Cells -- Aging -- Periodicals; Cells -- Aging; Oxidative stress; Oxidative Stress -- Periodicals; Cell Aging -- Periodicals; Periodicals; 611.0181
• DOI: 10.1155/2021/9912434
• Languages: English
• ISSNs: 1942-0900

Abstract

Abstract : 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 (Δ Ψ m ); 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.