No conflict of interest Effects of exercise on the cardiovascular system Cardiovascular Rehabilitation Training Course 22-23 March 2018, Lviv/Ukraine Dominique Hansen, FESC No conflict of interest

Learning objectives To obtain an understanding of the molecular impact of exercise on the vascular system To obtain an understanding of the molecular impact of exercise on the cardiomyocyte To understand the current limitations in this field of research To know what remains to be studied

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FBF: forearm blood flow

eNOS (endothelial NO synthase) activation is key to NO activation

Ca+-dependent vasodilation Step 1a: Ca+ inflow interacts with calmodulin, leading to eNOS release

Ca+-dependent vasodilation Step 1b: eNOS is attached to caveolin

Ca+-dependent vasodilation Step 2: eNOS associates with HSP-90 to prevent degradation

Ca+-dependent vasodilation Step 2: dimerization of the enzyme, leading to eNOS activation/NO production

VEGFR2 and PECAM1-dependent vasodilation (both mechanical receptors) Step 1: activation of cascade of different enzymes

VEGFR2 and PECAM1-dependent vasodilation (both mechanical receptors) Step 2: eNOS phosphorylation followed by NO production

Effects of Exercise Training on Left Ventricular Function and Peripheral Resistance in Patients With Chronic Heart Failure Hambrecht R, et al. JAMA 2000; 283: 3095-3101

Lowered blood pressure Improved vasodilation ?

Hyperactive Ubiquitin Proteasome System (UPS)

Exercise lowers UPS activity WR: Wistar Rat, EX: Exercise, SHR: spontaneous hypertensive

Impaired Ca+ handling Leads to disturbed excitation-contraction coupling Circulation Research. 2013;113:690-708

Improved Ca+ handling by exercise training

Cardiac remodelling

Improved cardiac remodelling by exercise training

Improved cardiac remodelling by exercise training

Enhanced angiogenesis

Autonomic function Ageing is associated with Β-adrenergic receptor desensitisation Probably due to long-term increased circulatory norepineprine concentrations Resulting into impaired Ca+ handling Leading to impaired inotropic and chronotropic responses

Myocardial fibrosis

Exercise training lowers fibrosis

Worse mitochondrial function by aging

Improved mitochondrial function by exercise

Improved mitochondrial function by exercise

What remains to be studied? Specific molecular cascades Exercise training modalities Strength training Exercise intensity Exercise volume Translation to humans Stress during exercise Genetic modification Male vs. female animals Interaction with drugs and diet

Conclusions Exercise training is capable to positively affect molecular mechanisms involved in: Vascular endothelial function Cardiomyocyte function These data should be interpreted in light of the study limitations