Seminars

Cardiovascular disease remains the number one cause of mortality and is fast becoming the number one health concern worldwide. Identification of new factors responsible for regulation of the cardiovascular system and generation of animal models of cardiovascular disease are important steps to better understand the pathogenesis of the heart failure including congenital heart disease and to develop new therapies. Prokineticins are small secreted bioactive peptides, comprising two classes: prokineticin-1 and prokineticin-2. They exert their biological activity through two G protein-coupled receptors: prokineticin receptor 1 (PKR1) and PKR2 to initiate their biological effects. Prokineticin-1 and prokineticin-2 share 58% amino acid identity. They are widely expressed among mammalian tissues. PKR1 and PKR2 share 85% amino acid identity and diverge mainly in their N-terminal sequences. PKR1 is mainly expressed in peripheral organs including heart, whereas PKR2 is mainly expressed in central nervous system. Up to now, known biological action of prokineticins are angiogenesis, gastrointestinal motility, hematopoiesis, reproductive system, endothelial survival, neuronal survival, olfactory bulb morphogenesis, Kallmann syndrome, gonadotropin-releaseing hormone neuron migration, pain sensitization, monocyte differentiation and macrophage activation, and circadian rhythms. However the role of prokineticins and their receptors in cardiovascular system have not studied before us. We have shown that PKR1 gene therapy after myocardial infarction improved survival rate and left ventricular function due to induction of anti-apoptosis effect and angiogenesis. Moreover, we have shown that cardiomyocyte specific PKR1 transgenic mice induced neo-vascularization through the activation of epicardial-derived progenitor cells (EPDC) in the heart. In the other hand, cardiomyocyte specific PKR2 transgenic mice showed hypertrophy and fenestration in blood vessels in the heart. Our results suggest that activation of PKR1 signaling or inhibition of PKR2 signaling can be beneficial for the treatment of myocardial infarction.