Circulating factors in regulation of cardiac function and stress response

This thesis studied circulating factors with potential as target for future heart failure drug development. The studies were conducted with suitable animal- and cell culture methods.

The thesis presents the circulating factor apela as a positive regulator of heart pumping function and heart circulation in the adult heart. The combination of effects is rare for a single substance and beneficial in treatment of heart failure.

Physical exercise has been known to have positive effects on heart function and growth. The mechanisms by which these beneficial effects happen are largely unknown. In this thesis, it was discovered that apelin is a central heart and skeletal muscle growth promoting circulating factor. In apelin knock out mice, physical exercise in apelin deprivation resulted in sickly weakness of the skeletal muscles. Skeletal muscle weakness is one of the most important factors in chronic disease or aging related loss of function.

In addition, the thesis discovered a novel way of protecting the heart from damage caused by lack of oxygen. The studies demonstrated that pharmacological inhibition of the activin type IIB receptor pre-conditions heart muscle cells for low oxygen conditions and resulted in less heart muscle damage due heart attack. Heart attack is one of most common causes for developing heart failure.

Heart failure is the fastest growing subclass of cardiovascular disease in the western world with no curative treatment available. This thesis brought novel insights into circulating factors regulating heart function and growth and created new openings for future drug development.