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Myocardial proteome changes in aortic stenosis rats subjected to long-term aerobic exercise

ABSTRACT: The effects of exercise training (ET) on the heart of aortic stenosis (AS) rats are controversial and the mechanisms involved in alterations induced by ET have been poorly clarified. In this study we analyzed the myocardial proteome to identify proteins modulated by moderate intensity aerobic ET in rats with chronic supravalvar AS. Wistar rats were divided into four groups: sedentary control (C-Sed), exercised control (C-Ex), sedentary aortic stenosis (AS-Sed), and exercised AS (AS-Ex). ET consisted of five treadmill running sessions per week for 16 weeks. Statistical analysis was performed by ANOVA or Kruskal-Wallis and Goodman tests. Results were discussed at a significance level of 5%. At the end of the experiment, AS-Ex rats had higher functional capacity, lower blood lactate concentration, and better cardiac structural and left ventricular functional parameters than the AS-Sed. Myocardial proteome analysis showed that AS-Sed had higher protein expressions related to the glycolytic pathway, oxidative stress, and inflammation, and lower protein expressions related to beta-oxidation than C-Sed. AS-Ex had higher expression of one protein related to mitochondrial biogenesis and lower protein expressions associated with oxidative stress and inflammation than AS-Sed. Proteomic data were validated for proteins related to lipid and glycolytic metabolism. In conclusion, chronic pressure overload changes the expression of myocardial proteins that are mainly involved in lipid and glycolytic energy metabolism in rats. Moderate intensity aerobic training attenuates protein expressions related to oxidative stress and inflammation and increases protein expressions related to mitochondrial biogenesis. Protein changes are associated with improved functional capacity, cardiac remodeling and left ventricular function in aortic stenosis rats.

INSTRUMENT(S): Xevo Q-Tof

ORGANISM(S): Rattus Norvegicus (rat)

TISSUE(S): Heart

SUBMITTER: Licia C. Silva-Costa

LAB HEAD: Gustavo Augusto

PROVIDER: PXD040785 | Pride | 2024-02-29

REPOSITORIES: Pride

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Project description:Background On-pump cardiac surgery provokes a predictable perioperative myocardial ischaemia–reperfusion injury which is associated with poor clinical outcomes. We determined the occurrence of time-of-the-day variation in perioperative myocardial injury in patients undergoing aortic valve replacement and its molecular mechanisms. Methods We studied the incidence of major adverse cardiac events in a prospective observational single-centre cohort study of patients with severe aortic stenosis and preserved left ventricular ejection fraction (>50%) who were referred to our cardiovascular surgery department at Lille University Hospital (Lille, France) for aortic valve replacement and underwent surgery in the morning or afternoon. Patients were matched into pairs by propensity score. We also did a randomised study, in which we evaluated perioperative myocardial injury and myocardial samples of patients randomly assigned (1:1) via permuted block randomisation (block size of eight) to undergo isolated aortic valve replacement surgery either in the morning or afternoon. We also evaluated human and rodent myocardium in ex-vivo hypoxia–reoxygenation models and did a transcriptomic analysis in myocardial samples from the randomised patients to identify the signalling pathway(s) involved. The primary objective of the study was to assess whether myocardial tolerance of ischaemia–reperfusion differed depending on the timing of aortic valve replacement surgery (morning vs afternoon), as measured by the occurrence of major adverse cardiovascular events (cardiovascular death, myocardial infarction, and admission to hospital for acute heart failure). The randomised study is registered with ClinicalTrials.gov, number NCT02812901. Findings In the cohort study (n=596 patients in matched pairs who underwent either morning surgery [n=298] or afternoon surgery [n=298]), during the 500 days following aortic valve replacement, the incidence of major adverse cardiac events was lower in the afternoon surgery group than in the morning group: hazard ratio 0·50 (95% CI 0·32–0·77; p=0·0021). In the randomised study, 88 patients were randomly assigned to undergo surgery in the morning (n=44) or afternoon (n=44); perioperative myocardial injury assessed with the geometric mean of perioperative cardiac troponin T release was significantly lower in the afternoon group than in the morning group (estimated ratio of geometric means for afternoon to morning of 0·79 [95% CI 0·68–0·93; p=0·0045]). Ex-vivo analysis of human myocardium revealed an intrinsic morning–afternoon variation in hypoxia–reoxygenation tolerance, concomitant with transcriptional alterations in circadian gene expression with the nuclear receptor Rev-Erbα being highest in the morning. In a mouse Langendorff model of hypoxia–reoxygenation myocardial injury, Rev-Erbα gene deletion or antagonist treatment reduced injury at the time of sleep-to-wake transition, through an increase in the expression of the ischaemia–reperfusion injury modulator CDKN1a/p21. Interpretation Perioperative myocardial injury is transcriptionally orchestrated by the circadian clock in patients undergoing aortic valve replacement, and Rev-Erbα antagonism seems to be a pharmacological strategy for cardioprotection. Afternoon surgery might provide perioperative myocardial protection and lead to improved patient outcomes compared with morning surgery.

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Myocardial proteome changes in aortic stenosis rats subjected to long-term aerobic exercise

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