Cyclocreatine protects against ischemic injury and enhances cardiac recovery during early reperfusion

Elgebaly, Salwa A.; Poston, Robert; Todd, Robert B.; Helmy, Tarek; Elbayoumi, Tamer; Kreutzer, Donald L.

doi:10.1080/14779072.2019.1662722

Cited by 16 publications

(39 citation statements)

References 67 publications

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“…Elgebaly et al [ 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 ] reported that Nourin is a potent inflammatory mediator rapidly released by human and animal hearts in response to reversible ischemic injury and necrosis. Nourin is a 3-KDa N-formyl peptide and its release by ischemic cardiac tissue is associated with post-ischemic cardiac inflammation in early ischemia/reperfusion animal models of cardiopulmonary bypass surgery and acute myocardial infarction (AMI) [ 6 ]. Nourin was purified from cardioplegic solutions collected during cardiac arrest from patients undergoing cardiopulmonary bypass for coronary revascularization [ 7 ], and its amino acid sequence was determined.…”

Section: Introductionmentioning

confidence: 99%

Nourin-Associated miRNAs: Novel Inflammatory Monitoring Markers for Cyclocreatine Phosphate Therapy in Heart Failure

Elgebaly

Todd²,

Kreutzer

et al. 2021

IJMS

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Background: Cyclocreatine phosphate (CCrP) is a potent bioenergetic cardioprotective compound known to preserve high levels of cellular adenosine triphosphate during ischemia. Using the standard Isoproterenol (ISO) rat model of heart failure (HF), we recently demonstrated that the administration of CCrP prevented the development of HF by markedly reducing cardiac remodeling (fibrosis and collagen deposition) and maintaining normal ejection fraction and heart weight, as well as physical activity. The novel inflammatory mediator, Nourin is a 3-KDa formyl peptide rapidly released by ischemic myocardium and is associated with post-ischemic cardiac inflammation. We reported that the Nourin-associated miR-137 (marker of cell damage) and miR-106b-5p (marker of inflammation) are significantly upregulated in unstable angina patients and patients with acute myocardial infarction, but not in healthy subjects. Objectives: To test the hypothesis that Nourin-associated miR-137 and miR-106b-5p are upregulated in ISO-induced “HF rats” and that the administration of CCrP prevents myocardial injury (MI) and reduces Nourin gene expression in “non-HF rats”. Methods: 25 male Wistar rats (180–220 g) were used: ISO/saline (n = 6), ISO/CCrP (0.8 g/kg/day) (n = 5), control/saline (n = 5), and control/CCrP (0.8 g/kg/day) (n = 4). In a limited study, CCrP at a lower dose of 0.4 g/kg/day (n = 3) and a higher dose of 1.2 g/kg/day (n = 2) were also tested. The Rats were injected SC with ISO for two consecutive days at doses of 85 and 170 mg/kg/day, respectively, then allowed to survive for an additional two weeks. CCrP and saline were injected IP (1 mL) 24 h and 1 h before first ISO administration, then daily for two weeks. Serum CK-MB (U/L) was measured 24 h after the second ISO injection to confirm myocardial injury. After 14 days, gene expression levels of miR-137 and miR-106b-5p were measured in serum samples using quantitative real-time PCR (qPCR). Results: While high levels of CK-MB were detected after 24 h in the ISO/saline rats indicative of MI, the ISO/CCrP rats showed normal CK-MB levels, supporting prevention of MI by CCrP. After 14 days, gene expression profiles showed significant upregulation of miR-137 and miR-106b-5p by 8.6-fold and 8.7-fold increase, respectively, in the ISO/saline rats, “HF rats,” compared to the control/saline group. On the contrary, CCrP treatment at 0.8 g/kg/day markedly reduced gene expression of miR-137 by 75% and of miR-106b-5p by 44% in the ISO/CCrP rats, “non-HF rats,” compared to the ISO/Saline rats, “HF rats.” Additionally, healthy rats treated with CCrP for 14 days showed no toxicity in heart, liver, and renal function. Conclusions: Results suggest a role of Nourin-associated miR-137 and miR-106b-5p in the pathogenesis of HF and that CCrP treatment prevented ischemic injury in “non-HF rats” and significantly reduced Nourin gene expression levels in a dose–response manner. The Nourin gene-based mRNAs may, therefore, potentially be used as monitoring markers of drug therapy response in HF, and CCrP—as a novel preventive therapy of HF due to ischemia.

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Section: Introductionmentioning

confidence: 99%

Nourin-Associated miRNAs: Novel Inflammatory Monitoring Markers for Cyclocreatine Phosphate Therapy in Heart Failure

Elgebaly

Todd²,

Kreutzer

et al. 2021

IJMS

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“…Nourin is a novel blood biomarker with a known mode of action as an early potent inflammatory mediator released within 5 min by ischemic myocardial tissue and it is associated with the initiation and amplification of post-ischemic cardiac inflammation [10][11][12][13][14][15]. Clinically high levels of Nourin were detected in ACS and AMI patients, but not in symptomatic noncardiac patients and healthy subjects [17], suggesting a potential use of the Nourin biomarker to rule out myocardial ischemia for symptomatic patients having noncardiac causes.…”

Section: Discussionmentioning

confidence: 99%

“…Elgebaly et al [10][11][12][13][14][15] reported that Nourin is a 3 KDa formyl peptide that is released within five minutes by human and animal hearts in response to ischemic injury. Nourin is unique because of its rapid release by reversible ischemic myocardium when cells are initially injured, but still alive and not dead.…”

Section: Introductionmentioning

confidence: 99%

“…A number of competitive antagonists were identified, including cyclosporin H, spinorphin, t-Boc-Phe-D.Leu-Phe-D.Leu-Phe, and soluble FPR fragment 17 aa loop peptide, which inhibited Nourin activity and tissue inflammation. Additionally, the bioenergetic compound, Cyclocreatine Phosphate (CCrP) prevented ischemic injury by preserving elevated levels of cellular adenosine triphosphate (ATP) during ischemia, thus reducing Nourin intracellular formation and circulating levels, resulting in reduction of early reperfusion cardiac inflammation and restoration of contractile function in animal models of AMI, global cardiac arrest, cardiopulmonary bypass, heart transplantation, as well as heart failure [10,13]. As a potent inflammatory mediator, Nourin stimulates leukocyte chemotaxis and VEC migration and activates human monocytes, neutrophils, and VECs to express high levels of cytokine storm mediators, digestive enzymes, and free radicals, including tumor necrosis factor-α (TNF-α, a key stimulant of apoptosis), interleukin 1β (IL-1β), interleukin 8 (IL-8), leukocyte-endothelial cell adhesion molecule 1 (LECAM-1), intercellular adhesion molecule 1 (ICAM-1), and endothelial-leukocyte adhesion molecule 1 (ELAM-1), as well as collagenase type IV, N-acetyl-B-glucosaminidase, gelatinases, and superoxide anion [10].…”

Section: Introductionmentioning

confidence: 99%

“…Several of these mediators were reported by other investigators to play a crucial role in recruiting and activating neutrophils during post-ischemic early reperfusion, and thus may contribute to the no-reflow phenomenon. Furthermore, since the above-described Nourin inhibitors/antagonists are aimed at controlling the level and activity of Nourin, they will likely reduce early post-reperfusion leukocyte influx/activation and inflammation-induced damage without interfering with the crucial cardiac repair process that occurs a few days following myocardial infarction [10]. Additionally, an independent study indicated that high levels of TNF-α, IL-1β, and IL-8 were detected in UA patients during the early disease phase [16], suggesting a role of Nourin-induced proinflammatory cytokines in the pathogenesis of UA.…”

Section: Introductionmentioning

confidence: 99%

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Nourin-Dependent miR-137 and miR-106b: Novel Early Inflammatory Diagnostic Biomarkers for Unstable Angina Patients

et al. 2021

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Background: Currently, no blood biomarkers exist that can diagnose unstable angina (UA) patients. Nourin is an early inflammatory mediator rapidly released within 5 min by reversible ischemic myocardium, and if ischemia persists, it is also released by necrosis. Nourin is elevated in acute coronary syndrome (ACS) patients but not in symptomatic noncardiac and healthy subjects. Recently, circulating microRNAs (miRNAs) have been established as markers of disease, including cardiac injury and inflammation. Objectives: To profile and validate the potential diagnostic value of Nourin-dependent miR-137 (marker of cell damage) and miR-106b-5p (marker of inflammation) as early biomarkers in suspected UA patients and to investigate the association of their target and regulating genes. Methods: Using Nourin amino acid sequence, an integrated bioinformatics analysis was conducted. Analysis indicated that Nourin is a direct target for miR-137 and miR-106b-5p in myocardial ischemic injury. Two linked molecular networks of lncRNA/miRNAs/mRNAs were also retrieved, including CTB89H12.4/miR-137/FTHL-17 and CTB89H12.4/miR-106b-5p/ANAPC11. Gene expression profiling was assessed in serum samples collected at presentation to an emergency department (ED) from: (1) UA patients (n = 30) (confirmed by invasive coronary angiography with stenosis greater than 50% and troponin level below the clinical decision limit); (2) patients with acute ST elevation myocardial infarction (STEMI) (n = 16) (confirmed by persistent ST-segment changes and elevated troponin level); and 3) healthy subjects (n = 16). Results: Gene expression profiles showed that miR-137 and miR-106b-5p were significantly upregulated by 1382-fold and 192-fold in UA compared to healthy, and by 2.5-fold and 4.6-fold in STEMI compared to UA, respectively. Healthy subjects showed minimal expression profile. Receiver operator characteristics (ROC) analysis revealed that the two miRNAs were sensitive and specific biomarkers for assessment of UA and STEMI patients. Additionally, Spearman’s correlation analysis revealed a significant association of miRNAs with the associated mRNA targets and the regulating lncRNA. Conclusions: Nourin-dependent gene expression of miR-137 and miR-106b-5p are novel blood-based biomarkers that can diagnose UA and STEMI patients at presentation and stratify severity of myocardial ischemia, with higher expression in STEMI compared to UA. Early diagnosis of suspected UA patients using the novel Nourin biomarkers is key for initiating guideline-based therapy that improves patients’ health outcomes.

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TREM2‐IGF1 Mediated Glucometabolic Enhancement Underlies Microglial Neuroprotective Properties During Ischemic Stroke

Yang,

Qin,

Chen

et al. 2023

Advanced Science

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Microglia, the major resident immune cells in the central nervous system, serve as the frontline soldiers against cerebral ischemic injuries, possibly along with metabolic alterations. However, signaling pathways involved in the regulation of microglial immunometabolism in ischemic stroke remain to be further elucidated. In this study, using single‐nuclei RNA sequencing, a microglial subcluster up‐regulated in ischemic brain tissues is identified, with high expression of Igf1 and Trem2, neuroprotective transcriptional signature and enhanced oxidative phosphorylation. Microglial depletion by PLX3397 exacerbates ischemic brain damage, which is reversed by repopulating the microglia with high Igf1 and Trem2 phenotype. Mechanistically, Igf1 serves as one of the major down‐stream molecules of Trem2, and Trem2‐Igf1 signaling axis regulates microglial functional and metabolic profiles, exerting neuroprotective effects on ischemic stroke. Overexpression of Igf1 and supplementation of cyclocreatine restore microglial glucometabolic levels and cellular functions even in the absence of Trem2. These findings suggest that Trem2‐Igf1 signaling axis reprograms microglial immunometabolic profiles and shifts microglia toward a neuroprotective phenotype, which has promising therapeutic potential in treating ischemic stroke.

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Cyclocreatine protects against ischemic injury and enhances cardiac recovery during early reperfusion

Cited by 16 publications

References 67 publications

Nourin-Associated miRNAs: Novel Inflammatory Monitoring Markers for Cyclocreatine Phosphate Therapy in Heart Failure

Nourin-Associated miRNAs: Novel Inflammatory Monitoring Markers for Cyclocreatine Phosphate Therapy in Heart Failure

Nourin-Dependent miR-137 and miR-106b: Novel Early Inflammatory Diagnostic Biomarkers for Unstable Angina Patients

TREM2‐IGF1 Mediated Glucometabolic Enhancement Underlies Microglial Neuroprotective Properties During Ischemic Stroke

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