Cardioprotective and Vasoprotective Effects of Corticotropin-Releasing Hormone and Urocortins: Receptors and Signaling

Abstract

Despite the recent progress in research and therapy, cardiovascular diseases are still the most common cause of death worldwide, thus new approaches are still needed. The aim of this review is to highlight the cardioprotective potential of urocortins and corticotropin-releasing hormone (CRH) and their signaling. It has been documented that urocortins and CRH reduce ischemic and reperfusion (I/R) injury, prevent reperfusion ventricular tachycardia and fibrillation, and improve cardiac contractility during reperfusion. Urocortin-induced increase in cardiac tolerance to I/R depends mainly on the activation of corticotropin-releasing hormone receptor-2 (CRHR2) and its downstream pathways including tyrosine kinase Src, protein kinase A and C (PKA, PKCε) and extracellular signal-regulated kinase (ERK1/2). It was discussed the possibility of the involvement of interleukin-6, Janus kinase-2 and signal transducer and activator of transcription 3 (STAT3) and microRNAs in the cardioprotective effect of urocortins. Additionally, phospholipase-A2 inhibition, mitochondrial permeability transition pore (MPT-pore) blockade and suppression of apoptosis are involved in urocortin-elicited cardioprotection. Chronic administration of urocortin-2 prevents the development of postinfarction cardiac remodeling. Urocortin possesses vasoprotective and vasodilator effect; the former is mediated by PKC activation and prevents an impairment of endothelium-dependent coronary vasodilation after I/R in the isolated heart, while the latter includes both cAMP and cGMP signaling and its downstream targets. As CRHR2 is expressed by both cardiomyocytes and vascular endothelial cells. Urocortins mediate both endothelium-dependent and -independent relaxation of coronary arteries.

Urocortin Role in Ischemia Cardioprotection and the Adverse Cardiac Remodeling

“…The three isoforms of Ucn have established protective actions against myocardial I/R since they attenuate I/R incidences and the consequent cardiac adverse remodeling. The early studies about Ucn highlighted its acute effects in Langendorff-perfused mice, rat, and sheep hearts or using isolated neonatal rat ventricular myocytes (NRVM) and adult cardiac myocytes (for a review, see [43]). The acute administration of Ucn before ischemia or at the onset of reperfusion improved cardiac hemodynamic parameters, decreased the infarct size, and attenuated apoptosis assessed by TUNEL staining, caspase activity, or lactate dehydrogenase (LDH) [44][45][46][47].…”

Functional characterization of two corticotropin-releasing hormone receptors in Larimichthys crocea

“…Mature CRH peptides have a high degree of conservation across teleosts, amphibians, and mammals and mediate various biological activities that affect reproductive behavior, cardiovascular regulation, appetite control, and immune function in addition to stress response (Grammatopoulos and Chrousos, 2002;Ma et al, 2020). Corresponding to its diverse biological functions, CRH is ubiquitously expressed in the central nervous system (CNS) and peripheral organs, such as the ovaries, heart, spleen, liver, and gastrointestinal tract (Wang et al, 2014;Popov et al, 2021).…”