Urocortin Role in Ischemia Cardioprotection and the Adverse Cardiac Remodeling

Abstract

Despite the considerable progress in strategies of myocardial protection, ischemic heart diseases (IHD) and consequent heart failure (HF) remain the main cause of mortality worldwide. Several procedures are used routinely to guarantee the prompt and successful reestablishment of blood flow to preserve the myocardial viability of infarcted hearts from ischemia injuries. However, ischemic heart reperfusion/revascularization triggers additional damages that occur when oxygen-rich blood re-enters the vulnerable myocardial tissue, which is a phenomenon known as ischemia and reperfusion (I/R) syndrome. Complications of I/R injuries provoke the adverse cardiac remodeling, involving inflammation, mishandling of Ca²⁺ homeostasis, apoptotic genes activation, cardiac myocytes loss, etc., which often progress toward HF. Therefore, there is an urgent need to develop new cardioprotective therapies for IHD and HF. Compelling evidence from animal studies and pilot clinical trials in HF patients suggest that urocortin (Ucn) isoforms, which are peptides associated with stress and belonging to the corticotropin releasing factor family, have promising potential to improve cardiovascular functions by targeting many signaling pathways at different molecular levels. This review highlights the current knowledge on the role of urocortin isoforms in cardioprotection, focusing on its acute and long-term effects.

Keywords: adverse cardiac remodeling; cardioprotection; heart failure; ischemia and reperfusion; urocortin.

Figure 1

Schematic model illustrating acute and long-term cardioprotection afforded by urocortin (Ucn) from I/R injuries. In heart, Ucn binds to CRFR2, which interacts with G-proteins activating different signaling pathways (PKC-MERK/ERK; cAMP-EPAC/PKA; PI3K/Akt) that acutely decrease cell death, improve Ca²⁺ handling, enhance cell survival, and improve cardiac function. Ucn also activates transcription factors and stimulates miRNAs, release which regulates the expression of genes related to apoptosis, fibrosis, hypertrophy, and Ca²⁺ homeostasis. The downregulation of these genes prevents the development of adverse cardiac remodeling, avoiding its progress toward heart failure.