1. Mitochondrial Reversible Changes Determine Diastolic Function Adaptations During Myocardial (Reverse) Remodeling
- Author
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Glória Conceição, Patrícia Rodrigues, Estela Alves, Inês Falcão-Pires, Adelino F. Leite-Moreira, Fabiana Baganha, Ana Catarina R. G. Fonseca, Tânia Lima, Francisco Vasques-Nóvoa, Alexandre Gonçalves, David Rizo, José Magalhães, Daniela Miranda-Silva, Isabel M. Miranda, and Cláudia Sousa
- Subjects
Male ,medicine.medical_specialty ,Oxidative phosphorylation ,030204 cardiovascular system & hematology ,Mitochondrion ,medicine.disease_cause ,Mitochondrial Dynamics ,Mitochondria, Heart ,Ventricular Function, Left ,Muscle hypertrophy ,03 medical and health sciences ,0302 clinical medicine ,Afterload ,Diastole ,Internal medicine ,Mitophagy ,medicine ,Animals ,Diastolic function ,Rats, Wistar ,Reverse remodeling ,030304 developmental biology ,0303 health sciences ,Ventricular Remodeling ,business.industry ,Recovery of Function ,Adaptation, Physiological ,Disease Models, Animal ,Oxidative Stress ,Cardiology ,Hypertrophy, Left Ventricular ,Energy Metabolism ,Cardiology and Cardiovascular Medicine ,business ,Oxidative stress - Abstract
Background: Often, pressure overload–induced myocardial remodeling does not undergo complete reverse remodeling after decreasing afterload. Recently, mitochondrial abnormalities and oxidative stress have been successively implicated in the pathogenesis of several chronic pressure overload cardiac diseases. Therefore, we aim to clarify the myocardial energetic dysregulation in (reverse) remodeling, mainly focusing on the mitochondria. Methods: Thirty-five Wistar Han male rats randomly underwent sham or ascending (supravalvular) aortic banding procedure. Echocardiography revealed that banding induced concentric hypertrophy and diastolic dysfunction (early diastolic transmitral flow velocity to peak early-diastolic annular velocity ratio, E/E′: sham, 13.6±2.1, banding, 18.5±4.1, P =0.014) accompanied by increased oxidative stress (dihydroethidium fluorescence: sham, 1.6×10 8 ±6.1×10 7 , banding, 2.6×10 8 ±4.5×10 7 , P Results: Two weeks later, hypertrophy decreased with the decline of oxidative stress (dihydroethidium fluorescence: banding, 2.6×10 8 ±4.5×10 7 , debanding, 1.96×10 8 ±6.8×10 7 , P P =0.029). The reduction of energetic demands imposed by overload relief allowed the mitochondria to reduce its activity and myocardial levels of phosphocreatine, phosphocreatine/ATP, and ATP/ADP to normalize in debanding towards sham values (phosphocreatine: sham, 38.4±7.4, debanding, 35.6±8.7, P =0.71; phosphocreatine/ATP: sham, 1.22±0.23 debanding, 1.11±0.24, P =0.59; ATP/ADP: sham, 6.2±0.9, debanding, 5.6±1.6, P =0.66). Despite the decreased mitochondrial area, complex III and V expression increased in debanding compared with sham or banding. Autophagy and mitophagy-related markers increased in banding and remained higher in debanding rats. Conclusions: During compensatory and maladaptive hypertrophy, mitochondria become more active. However, as the disease progresses, the myocardial energetic demands increase and the myocardium becomes energy deficient. During reverse remodeling, the concomitant attenuation of cardiac hypertrophy and oxidative stress allowed myocardial energetics, left ventricle hypertrophy, and diastolic dysfunction to recover. Autophagy and mitophagy are probably involved in the myocardial adaptation to overload and to unload. We conclude that these mitochondrial reversible changes underlie diastolic function adaptations during myocardial (reverse) remodeling.
- Published
- 2020