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 (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 Ca2+-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 Ca2+ 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.
Highlights
Pulmonary arterial hypertension (PAH) is a complex disease resulted from the interplay of several biological and environmental processes leading to pulmonary vasculature remodeling, pulmonary hypertension [1]
right ventricular (RV) myocyte function was evaluated by characterizing cell contraction and Ca2+ dynamics to assess alterations in excitation-contraction coupling (ECC)
We found a strong relationship between preservation of mitochondrial function and cyclophilin D (CypD) acetylation via SIRT3, loss and gain of function experiments can assess its definitive role in this model
Summary
Pulmonary arterial hypertension (PAH) is a complex disease resulted from the interplay of several biological and environmental processes leading to pulmonary vasculature remodeling, pulmonary hypertension [1]. RV hypertrophy is a necessary adaptation to preserve RVpulmonary arterial coupling by decreasing RV wall tension and increasing RV cardiomyocyte force-generating capacity. A polyphenol from the stilbene family, 3,5,4′-trihydroxystilbene resveratrol (RES), has drawn researchers’ attention by its cardioprotective activity in other cardiovascular diseases [5]. In PAH models, RES improves lung functioning through its antiproliferative [9], antioxidant [10], and anti-inflammatory properties [11]. RES activates sirtuins, a relevant group of deacetylases that participate in the regulation of numerous cellular processes [12]. Sirtuin activation has been linked to the prevention of hypertrophy [13] and energetic dysfunction [14, 15]
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