Targets identified from exercised heart: killing multiple birds with one stone

Abstract

Cardiovascular diseases (CVDs) are a major cause of mortality worldwide, which are mainly driven by factors such as aging, sedentary lifestyle, and excess alcohol use. Exercise targets several molecules and protects hearts against many of these physiological and pathological stimuli. Accordingly, it is widely recognized as an effective therapeutic strategy for CVD. To investigate the molecular mechanism of exercise in cardiac protection, we identify and describe several crucial targets identified from exercised hearts. These targets include insulin-like growth factor 1 (IGF1)-phosphatidylinositol 3 phosphate kinase (PI3K)/protein kinase B (AKT), transcription factor CCAAT/enhancer-binding protein β (C/EBPβ), cardiac microRNAs (miRNAs, miR-222 and miR-17-3p etc.), exosomal-miRNAs (miR-342, miR-29, etc.), Sirtuin 1 (SIRT1), and nuclear factor erythroid 2‑related factor/metallothioneins (Nrf2/Mts). Targets identified from exercised hearts can alleviate injury via multiple avenues, including: (1) promoting cardiomyocyte proliferation; (2) facilitating cardiomyocyte growth and physiologic hypertrophy; (3) elevating the anti-apoptotic capacity of cardiomyocytes; (4) improving vascular endothelial function; (5) inhibiting pathological remodeling and fibrosis; (6) promoting extracellular vesicles (EVs) production and exosomal-molecules transfer. Exercise is one treatment (‘stone’), which is cardioprotective via multiple avenues (‘birds’), and is considered ‘killing multiple birds with one stone’ in this review. Further, we discuss the potential application of EV cargos in CVD treatment. We provide an outline of targets identified from the exercised heart and their mechanisms, as well as novel ideas for CVD treatment, which may provide novel direction for preclinical trials in cardiac rehabilitation.

Animal exercise studies in cardiovascular research: Current knowledge and optimal design—A position paper of the Committee on Cardiac Rehabilitation, Chinese Medical Doctors’ Association

“…Increasing evidence indicates that targets identified in exercised animal hearts have the potential to mitigate cardiac injury in multiple ways. 176 Molecules that are regulated in exercised animal hearts may promote physiological hypertrophy of cardiomyocytes and may have the potential to enhance the expression of proliferation markers of cardiomyocytes and prevent cardiomyocyte apoptosis as well. 9 …”

“… 92 , 98 , 175 , 179 A deep understanding of the functions and mechanisms of exercise-responsive molecules paves the way for identifying novel myocardial protective or therapeutic targets for CVDs. 8 , 137 , 176 …”

Exercise-induced signaling pathways to counteracting cardiac apoptotic processes

“…Of these, physical activity is one of the most important because aerobic exercise (70–75% VO 2max ) makes the heart resistant to myocardial infarction in rats ( Alizadeh Pahavani et al, 2020 ). A scientific study of more than 3,000 people found that aerobic exercise reduced hospitalization due to heart failure as well as cardiovascular events ( Mediano et al, 2018 ; Wang et al, 2021 ). Other studies have shown that aerobic exercise (Equivalent to 70–75% VO 2max ) increases anti-apoptotic factors such as B-cell lymphoma 2 (Bcl-2) and decreases apoptotic factors such as BCL2 associated X (Bax) in the myocardium.…”

Lymphangiogenesis: A new player in the heart's adaptive response to exercise

“…Thus, understanding the mechanisms by which exercise induces physiological hypertrophy and cardioprotection will inform the development of exercise interventions and exercise-based therapeutics for the treatment of cardiovascular disease. 8 , 9 …”