Reperfusion therapy with recombinant human relaxin-2 (Serelaxin) attenuates myocardial infarct size and NLRP3 inflammasome following ischemia/reperfusion injury via eNOS-dependent mechanism

Raleigh, Juan Valle; Mauro, Adolfo G; Devarakonda, Teja; Marchetti, Carlo; He, Jun; Kim, Erica; Filippone, Scott M.; Das, Anindita; Toldo, Stefano; Abbate, Antonio; Salloum, Fadi N.

doi:10.1093/cvr/cvw246

Cited by 69 publications

(77 citation statements)

References 40 publications

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“…Increasing evidences suggested that phosphorylation of eNOS, the target of Akt, was an important downstream effector in survival signaling in cardiomyocytes . Raleigh et al demonstrated that recombinant human relaxin‐2 (serelaxin) protects myocardium against I‐R injury by eNOS activation, while eNOS knock out abolished serelaxin's beneficial effects. Our results also showed that hydromorphine exhibited significant effect of increases in the levels of both p‐eNOS and NO in the isolated perfused heart following I/R injury compared with sham group.…”

Section: Discussionmentioning

confidence: 99%

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Hydromorphine postconditioning protects isolated rat heart against ischemia‐reperfusion injury via activating P13K/Akt/eNOS signaling

Liu

et al. 2018

Cardiovascular Therapeutics

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Summary Introduction Myocardial ischemia/reperfusion injury (myocardial I/R injury) has a high disability rate and mortality. Novel treatments for myocardial I/R injury are necessary. Aim In order to explore the protective effect of hydromorphine on myocardial I/R injury, we illuminate the underlying mechanism of the protective effect. Results Hydromorphine significantly reduced myocardial infarct size (IFN/AAR), CKMB (Creatine Kinase MB) and TN‐T (Troponin T) release, and improved cardiac function compared with I/R group. However, these advantageous effects were partly suppressed in the presence of hydromorphine. Myocardial I/R injury significantly decreased the phosphorylation of Akt and eNOS, and down‐regulated total nitric oxide and nitrotyrosine content, while these inhibitory effects were partly abolished by hydromorphine. Conversely, the activated effects of hydromorphine on the phosphorylation of Akt and eNOS, and NO release were totally reversed by LY294002, which, used individually, show the same influence on reperfusion injury. Conclusions These findings suggest that hydromorphine postconditioning may protect isolated rat heart against reperfusion injury via activating P13K/Akt/eNOS signaling.

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Section: Discussionmentioning

confidence: 99%

“…28 Increasing evidences suggested that phosphorylation of eNOS, the target of Akt, was an important downstream effector in survival signaling in cardiomyocytes. [29][30][31] Raleigh et al 32 to myocardial injury by nitrative stress. 35,36 Thereby, these findings may on account of different disease models, type, and dose of drugs.…”

Section: Discussionmentioning

confidence: 99%

Hydromorphine postconditioning protects isolated rat heart against ischemia‐reperfusion injury via activating P13K/Akt/eNOS signaling

Liu

et al. 2018

Cardiovascular Therapeutics

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“…In the phase 3 RELAX‐AHF (Serelaxin, Recombinant Human Relaxin‐2, for Treatment of Acute Heart Failure) trial of patients with acute heart failure, those who received a 16‐hour infusion of serelaxin showed improvements in biomarker expression patterns reflecting cardiac, renal, and hepatic damage, and these improvements correlated with reductions in all‐cause mortality by day 180 39, 41. In animal models, serelaxin and other formulations of recombinant relaxin‐2 have been shown to be protective in experimental models of cardiac injury 15, 16, 17, 18, 42, 43…”

Section: Discussionmentioning

confidence: 99%

Relaxin Family Member Insulin‐Like Peptide 6 Ameliorates Cardiac Fibrosis and Prevents Cardiac Remodeling in Murine Heart Failure Models

Maruyama

Yoshida

et al. 2018

JAHA

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BackgroundThe insulin/insulin‐like growth factor/relaxin family represents a group of structurally related but functionally diverse proteins. The family member relaxin‐2 has been evaluated in clinical trials for its efficacy in the treatment of acute heart failure. In this study, we assessed the role of insulin‐like peptide 6 (INSL6), another member of this protein family, in murine heart failure models using genetic loss‐of‐function and protein delivery methods.Methods and ResultsInsl6‐deficient and wild‐type (C57BL/6N) mice were administered angiotensin II or isoproterenol via continuous infusion with an osmotic pump or via intraperitoneal injection once a day, respectively, for 2 weeks. In both models, Insl6‐knockout mice exhibited greater cardiac systolic dysfunction and left ventricular dilatation. Cardiac dysfunction in the Insl6‐knockout mice was associated with more extensive cardiac fibrosis and greater expression of fibrosis‐associated genes. The continuous infusion of chemically synthesized INSL6 significantly attenuated left ventricular systolic dysfunction and cardiac fibrosis induced by isoproterenol infusion. Gene expression profiling suggests liver X receptor/retinoid X receptor signaling is activated in the isoproterenol‐challenged hearts treated with INSL6 protein.ConclusionsEndogenous Insl6 protein inhibits cardiac systolic dysfunction and cardiac fibrosis in angiotensin II– and isoproterenol‐induced cardiac stress models. The administration of recombinant INSL6 protein could have utility for the treatment of heart failure and cardiac fibrosis.

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“…17,18) Notably, recent pilot clinical trials also suggested a protective role of RLX-2 for ischemic heart disease by indicating that RLX-2 administration was associated with increased myocardial salvage and improved ventricular remodeling. 19,20) These results suggested that RLX-2 may prove essential in the initial and progressing glucose metabolism dysfunction related CVDs.…”

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confidence: 84%

Decreased Serum Relaxin-2 Is Correlated with Impaired Islet β-Cell Function in Patients with Unstable Angina and Abnormal Glucose Metabolism

Gao

Wang

et al. 2018

Int. Heart J.

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SummaryCirculating relaxin (RLX) is altered in patients with diabetes mellitus (DM) or cardiovascular diseases. This study was designed to evaluate the changes of RLX in patients with unstable angina (UA) complicated with various categories of abnormal glucose metabolism.Patients who confirmed UA by angiographic and clinical standard were grouped according to the glucose metabolism status with oral glucose tolerance test (OGTT) and medical history categorized as normal, prediabetes, newly diagnosed type 2 DM (T2DM), and previously diagnosed T2DM. Serum RLX-2 was measured and islet β-cell function was evaluated. The severity of the coronary arterial lesions was evaluated with Syntax Scores.Serum RLX-2 was significantly higher in UA patients with prediabetes (median [quartiles]: 9.87 [7.48, 32.58] pg/mL) and newly diagnosed T2DM (18.36 [9.52, 48.08] pg/mL), compared with those with normal glucose tolerance (6.24 [4.02, 7.27] pg/mL, both P < 0.05). Interestingly, UA patients with previously diagnosed T2DM exhibited lower RLX-2 levels (4.17 [3.23, 5.72] pg/mL) compared with those with normal glucose tolerance (P < 0.05). Subsequent analyses indicated that serum RLX-2 was positively associated with parameters of islet β-cell function, C-peptide, and fasting insulin levels; however, it was negatively associated with the levels of fasting glucose, 2-hour postprandial blood glucose, HbA1c, and insulin sensitivity, suggesting a potential protective role of RLX-2 during abnormal glucose metabolism in UA patients. Serum RLX-2 was not correlated with the Syntax Scores in these patients.Serum RLX-2 is a potential marker for UA patients with early glucose metabolism abnormality, and increased RLX-2 level was correlated with preserved islet β-cell function.(Int Heart J Advance Publication)

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Reperfusion therapy with recombinant human relaxin-2 (Serelaxin) attenuates myocardial infarct size and NLRP3 inflammasome following ischemia/reperfusion injury via eNOS-dependent mechanism

Abstract: Serelaxin attenuates myocardial I/R injury and the subsequent caspase-1 activation via eNOS-dependent mechanism.

Cited by 69 publications

References 40 publications

Hydromorphine postconditioning protects isolated rat heart against ischemia‐reperfusion injury via activating P13K/Akt/eNOS signaling

Hydromorphine postconditioning protects isolated rat heart against ischemia‐reperfusion injury via activating P13K/Akt/eNOS signaling

Relaxin Family Member Insulin‐Like Peptide 6 Ameliorates Cardiac Fibrosis and Prevents Cardiac Remodeling in Murine Heart Failure Models

Decreased Serum Relaxin-2 Is Correlated with Impaired Islet β-Cell Function in Patients with Unstable Angina and Abnormal Glucose Metabolism

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