Cyclocreatine Phosphate: A Novel Bioenergetic/Anti-Inflammatory Drug That Resuscitates Poorly Functioning Hearts and Protects against Development of Heart Failure

Abstract

Irreversible myocardial injury causes the exhaustion of cellular adenosine triphosphate (ATP) contributing to heart failure (HF). Cyclocreatine phosphate (CCrP) was shown to preserve myocardial ATP during ischemia and maintain cardiac function in various animal models of ischemia/reperfusion. We tested whether CCrP administered prophylactically/therapeutically prevents HF secondary to ischemic injury in an isoproterenol (ISO) rat model. Thirty-nine rats were allocated into five groups: control/saline, control/CCrP, ISO/saline (85 and 170 mg/kg/day s.c. for 2 consecutive days), and ISO/CCrP (0.8 g/kg/day i.p.) either administrated 24 h or 1 h before ISO administration (prophylactic regimen) or 1 h after the last ISO injection (therapeutic regimen) and then daily for 2 weeks. CCrP protected against ISO-induced CK-MB elevation and ECG/ST changes when administered prophylactically or therapeutically. CCrP administered prophylactically decreased heart weight, hs-TnI, TNF-α, TGF-β, and caspase-3, as well as increased EF%, eNOS, and connexin-43, and maintained physical activity. Histology indicated a marked decrease in cardiac remodeling (fibrin and collagen deposition) in the ISO/CCrP rats. Similarly, therapeutically administered CCrP showed normal EF% and physical activity, as well as normal serum levels of hs-TnI and BNP. In conclusion, the bioenergetic/anti-inflammatory CCrP is a promising safe drug against myocardial ischemic sequelae, including HF, promoting its clinical application to salvage poorly functioning hearts.

Integrated Bioinformatics Analysis Confirms the Diagnostic Value of Nourin-Dependent miR-137 and miR-106b in Unstable Angina Patients

“…Nourin, a 3 KDa formyl peptide, has emerged as a pivotal factor in the context of myocardial ischemia [6][7][8]. This is because of its rapid release by the heart muscle during the early stages of reversible myocardial ischemia, which has generated interest in its potential application for the rapid diagnosis of UA patients before progressing to AMI [6][7][8].…”

“…Nourin, a 3 KDa formyl peptide, has emerged as a pivotal factor in the context of myocardial ischemia [6][7][8]. This is because of its rapid release by the heart muscle during the early stages of reversible myocardial ischemia, which has generated interest in its potential application for the rapid diagnosis of UA patients before progressing to AMI [6][7][8]. Serving as a potent inflammatory mediator, Nourin initiates and propagates cardiac inflammation after ischemic events in animal models of heart failure [7,8], cardiopulmonary bypass surgery (reversible ischemia), and myocardial infarction [6].…”

“…This is because of its rapid release by the heart muscle during the early stages of reversible myocardial ischemia, which has generated interest in its potential application for the rapid diagnosis of UA patients before progressing to AMI [6][7][8]. Serving as a potent inflammatory mediator, Nourin initiates and propagates cardiac inflammation after ischemic events in animal models of heart failure [7,8], cardiopulmonary bypass surgery (reversible ischemia), and myocardial infarction [6]. These discoveries emphasize the importance of uncovering mechanisms that regulate Nourin-induced ischemic damage and inflammation and its subsequent impacts.…”