Lymphangiogenesis contributes to exercise-induced physiological cardiac growth

Background:Promoting cardiac lymphangiogenesis exerts beneficial effects for the heart.Exercise can induce physiological cardiac growth with cardiomyocyte hypertrophy and increased proliferation markers in cardiomyocytes.However,it remains unclear whether and how lymphangiogenesis contributes to exercise-induced physiological cardiac growth.We aimed to investigate the role and mechanism of lymphangiogenesis in exercise-induced physiological cardiac growth.Methods:Adult C57 BL6/J mice were subjected to 3 weeks of swimming exercise to induce physiological cardiac growth.Oral treatment with vascular endothelial growth factor receptor 3(VEGFR3) inhibitor SAR1 3 1 675 was used to investigate whether cardiac lymphangiogenesis was required for exercise-induced physiological cardiac growth by VEGFR3 activation.Furthermore,human dermal lymphatic endothelial cell(LEC)-conditioned medium was collected to culture isolated neonatal rat cardiomyocytes to determine whether and how LECs could influence cardiomyocyte proliferation and hypertrophy.Results:Swimming exercise induced physiological cardiac growth accompanied by a remarkable increase of cardiac lymphangiogenesis as evidenced by increased density of lymphatic vessel endothelial hyaluronic acid receptor 1-positive lymphatic vessels in the heart and upregulated LYVE-1 and Podoplanin expressions levels.VEGFR3 was upregulated in the exercised heart,while VEGFR3 inhibitor SAR131675 attenuated exercise-induced physiological cardiac growth as evidenced by blunted myocardial hypertrophy and reduced proliferation marker Ki67 in cardiomyocytes,which was correlated with reduced lymphatic vessel density and downregulated LYVE-1 and Podoplanin in the heart upon exercise.Furthermore,LEC-conditioned medium promoted both hypertrophy and proliferation of cardiomyocytes and contained higher levels of insulinlike growth factor-1 and the extracellular protein Reelin,while LEC-conditioned medium from LECs treated with SAR131675 blocked these effects.Functional rescue assays further demonstrated that protein kinase B(AKT) activation,as well as reduced CCAAT enhancer-binding protein beta(C/EBPβ) and increased CBP/p300-interacting transactivators with E(glutamic acid)/D(aspartic acid)-rich-carboxylterminal domain 4(CITED4),contributed to the promotive effect of LEC-conditioned medium on cardiomyocyte hypertrophy and proliferation.Conclusion:Our findings reveal that cardiac lymphangiogenesis is required for exercise-induced physiological cardiac growth by VEGFR3 activation,and they indicate that LEC-conditioned medium promotes both physiological hypertrophy and proliferation of cardiomyocytes through AKT activation and the C/EBPβ-CITED4 axis.These results highlight the essential roles of cardiac lymphangiogenesis in exercise-induced physiological cardiac growth.

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

Growing evidence has demonstrated exercise as an effective way to promote cardiovascular health and protect against cardiovascular diseases However,the underlying mechanisms of the beneficial effects of exercise have yet to be elucidated.Animal exercise studies are widely used to investigate the key mechanisms of exercise-induced cardiovascular protection.However,standardized procedures and well-established evaluation indicators for animal exercise models are needed to guide researchers in carrying out effective,high-quality animal studies using exercise to prevent and treat cardiovascular diseases.In our review,we present the commonly used animal exercise models in cardiovascular research and propose a set of standard procedures for exercise training,emphasizing the appropriate measurements and analysis in these chronic exercise models.We also provide recommendations for optimal design of animal exercise studies in cardiovascular research,including the choice of exercise models,control of exercise protocols,exercise at different stages of disease,and other considerations,such as age,sex,and genetic background.We hope that this position paper will promote basic research on exercise-induced cardiovascular protection and pave the way for successful translation of exercise studies from bench to bedside in the prevention and treatment of cardiovascular diseases.

Exercise training maintains cardiovascular health:signaling pathways involved and potential therapeutics

Exercise training has been widely recognized as a healthy lifestyle as well as an effective non-drug therapeutic strategy for cardiovascular diseases(CVD).Functional and mechanistic studies that employ animal exercise models as well as observational and interventional cohort studies with human participants,have contributed considerably in delineating the essential signaling pathways by which exercise promotes cardiovascular fitness and health.First,this review summarizes the beneficial impact of exercise on multiple aspects of cardiovascular health.We then discuss in detail the signaling pathways mediating exercise’s benefits for cardiovascular health.The exercise-regulated signaling cascades have been shown to confer myocardial protection and drive systemic adaptations.The signaling molecules that are necessary for exercise-induced physiological cardiac hypertrophy have the potential to attenuate myocardial injury and reverse cardiac remodeling.Exercise-regulated noncoding RNAs and their associated signaling pathways are also discussed in detail for their roles and mechanisms in exercise-induced cardioprotective effects.Moreover,we address the exercise-mediated signaling pathways and molecules that can serve as potential therapeutic targets ranging from pharmacological approaches to gene therapies in CVD.We also discuss multiple factors that influence exercise’s effect and highlight the importance and need for further investigations regarding the exercise-regulated molecules as therapeutic targets and biomarkers for CVD as well as the cross talk between the heart and other tissues or organs during exercise.We conclude that a deep understanding of the signaling pathways involved in exercise’s benefits for cardiovascular health will undoubtedly contribute to the identification and development of novel therapeutic targets and strategies for CVD.

Downregulation of circ-ZNF609 Promotes Heart Repair by Modulating RNA N^(6)-Methyladenosine-Modified Yap Expression

Circular RNAs take crucial roles in several pathophysiological processes.The regulatory role and its underlying mechanisms of circ-ZNF609 in the heart remains largely unknown.Here,we report that circ-ZNF609 is upregulated during myocardial ischemia/reperfusion(I/R)remodeling.Knockdown of circ-ZNF609 protects against acute I/R injury and attenuates left ventricle dysfunction after I/R remodeling in vivo.In vitro,circ-ZNF609 regulates cardiomyocyte survival and proliferation via modulating the crosstalk between Hippo-YAP and Akt signaling.Mechanically,N6-methyladenosine-modification is involved in the regulatory role of circ-ZNF609 on YAP.An in-depth study indicates that knockdown of circ-ZNF609 decreases the expression of YTHDF3 and further fine-tuned the accessibility of Yap mRNA to YTHDF1 and YTHDF2 to regulate YAP expression.circ-ZNF609 knockdown represents a promising therapeutic strategy to combat the pathological process of myocardial I/R injury.