Abstract Body: Background: Despite advances in treatment, myocardial infarction often leads to heart failure (HF). Aerobic exercise training (AET) is known to mitigate HF’s harmful effects. Long non-coding RNAs (lncRNAs) have emerged as promising therapeutic targets in cardiovascular diseases. However, the combined therapeutic potential of AET and lncRNA modulation in HF remains largely unexplored.
Aim: To investigate the role of AET on lncRNA expression in Wistar rats with ischemic HF.
Methods: Thirty male and female Wistar rats (8 wk-old) were subjected to left coronary artery ligation to induce HF or sham surgery. HF was confirmed after 4 wks. Animals were divided into sedentary sham (SS), HF sedentary (HF), and HF trained (HF-T). AET consisted of treadmill running (10 wks, 60 min/session, 1x/day, 5x/wk, at 60% peak oxygen uptake (VO₂ peak)). Post-AET, echocardiography and exercise tolerance were assessed. lncRNA expression (RNA sequencing and RT-qPCR) was analyzed in the remote infarcted left ventricle (IACUC-USP-No.2023/01). In vitro, H9c2 cells were treated with isoproterenol (ISO, 20 µM) or IGF-1 (50 ng/mL) for 48 h, and morphological and molecular alterations were analyzed. Statistical analyses: one-way ANOVA followed by Tukey’s test. Results were presented as mean ± SEM.
Results: At the end of the protocol, the HF group exhibited reduced ejection fraction (31±2%) and increased cardiac mass (1,003±110mg), pulmonary edema and exercise intolerance (VO₂ peak: 58.3±2.1mL^.kg^-1.min^-1) compared with the SS group (80±1%; 733±103mg; 66.2±1.0mL^.kg^-1.min^-1; p<0.05). AET improved cardiac function (59±2%), and attenuated hypertrophy (845±98mg), and exercise intolerance (68.6±2.5mL^.kg^-1.min^-1) in HF-T. RNA sequencing identified 301 lncRNAs differentially expressed in HF compared with SS (220 up and 81 down). Among these, 84 were restored in HF-T and 25 showed conserved homology with human sequences (14 up/11 down). Validation identified four with altered expression in HF restored by AET independent of sex (NONRATT-5839, -19610, -15795, -1295). In vitro, ISO treatment induced hypertrophy, HF markers and significantly modulated lncRNA expression, reproducing in vivo pattern. IGF-1 pretreatment exerted a cardioprotective effect and restored lncRNA expression compared with ISO alone in H9c2 cells.
Conclusion: AET improved cardiac phenotype, function, and exercise tolerance in HF rats while normalizing key lncRNA expression, highlighting its potential as a therapeutic strategy for HF.