Cardiomyocytic apoptosis limited by bradykinin via restoration of nitric oxide after cardioplegic arrest.
ABSTRACT Our previous studies revealed that cardioplegia-induced cardiac arrest under cardiopulmonary bypass (CPB) decreased cardiomyocytic nitric oxide and increased apoptosis. We hypothesized that pretreatment with bradykinin (BK) would improve the profile of anti-apoptotic proteins and inhibit cardiomyocytic apoptosis.
New Zealand white rabbits received total CPB. Rabbits were weaned from CPB and reperfused for 4 h. Blood was sampled at various time points. Bradykinin and/or nitric oxide synthase (NOS) inhibitors or BK-receptor antagonists were infused systemically 30 min before beginning of CPB, and continued throughout the procedure. The ascending aorta was cross-clamped for 60 min while cold crystalloid cardioplegic solution was intermittently infused into the aortic root. The hearts were harvested and studied for evidence of apoptosis and ischemia/reperfusion induced inflammation-related cytokine production by cardiomyocytes.
Our results revealed that bradykinin supplementation during cardioplegia could prevent I/R-induced inflammatory and apoptotic effects, which could be reversed with a NOS inhibitor. BK antagonists and NOS inhibitors worsened the inflammatory and apoptotic responses of cardiomyocytes, which could be reversed with an exogenous NO donor.
Restoring the NO concentration after cardioplegia-induced cardiac arrest (CCA) under CPB with bradykinin could modulate (1) the nuclear translocation of NF-kappaB, (2) the plasma levels of inflammation-related cytokines, (3) the Bcl-2/Bax ratio, and (4) the occurrence of apoptosis. Exogenous bradykinin administration was associated with the myocardial apoptotic response by inhibition of NF-kappaB translocation, inflammatory cytokine production, Akt activation, and elevation of the Bcl-2/Bax ratio via a NO-mediated pathway.
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ABSTRACT: One of the most common health problems are diseases of the cardiovascular system with a great bulk of disease burden; while a considerable number of cardiac patients undergo cardiac surgery; cardiac surgical procedures with cardiopulmonary bypass (CPB) are nowadays among the top list of surgical procedures. More than half of a century has passed since the introduction of total cardiopulmonary bypass (CPB). One of the main untoward effects of CPB is systemic inflammation; causing an "acute phase reaction" responsible for the production of other unwanted postoperative complications. The humoral and cellular components of the immune system are among the main parts of these compensatory mechanisms. There are a number of therapeutic agents used to suppress this inflammatory process. Since CPB is composed of a multitude of items, there are many studies assessing the possible methods and therapeutics for prevention or treatment of inflammation in patients undergoing CPB. According to a conventional classification, the anti-inflammatory methods are classified as either pharmacologic strategies or technical strategies. The pharmacologic strategies are those with the usage of one or more therapeutic agents; while the technical strategies are those that try to modify the CPB techniques. However, in this manuscript, the main pharmacological strategies are discussed.Iranian journal of pharmaceutical research (IJPR) 03/2012; 11(3):705-14. · 0.51 Impact Factor
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ABSTRACT: Stem cell preconditioning (PC) is a powerful approach in reducing cell death after transplantation. We hypothesized that PC human endothelial progenitor cells (hEPCs) with bradykinin (BK) enhance cell survival, inhibit apoptosis and repair the infarcted myocardium. The hEPCs were preconditioned with or without BK. The hEPCs apoptosis induced by hypoxia along with serum deprivation was determined by annexin V-fluorescein isothiocyanate/ propidium iodide staining. Cleaved caspase-3, Akt and eNOS expressions were determined by Western blots. Caspase-3 activity and vascular endothelial growth factor (VEGF) levels were assessed in hEPCs. For in vivo studies, the survival and cardiomyocytes apoptosis of transplanted hEPCs were assessed using 1,1'-dioctadecyl-3,3,3',3'-tetramethylindodi- carbocyanine,4-chlorobenzenesul-fonate salt labeled hEPCs and TUNEL staining. Infarct size and cardiac function were measured at 10 days after transplantation, and the survival of transplanted hEPCs were visualized using near-infrared optical imaging. In vitro data showed a marked suppression in cell apoptosis following BK PC. The PC reduced caspase-3 activation, increased the Akt, eNOS phosphorylation and VEGF levels. In vivo data in preconditioned group showed a robust cell anti-apoptosis, reduction in infarct size, and significant improvement in cardiac function. The effects of BK PC were abrogated by the B2 receptor antagonist HOE140, the Akt and eNOS antagonists LY294002 and L-NAME, respectively. The activation of B2 receptor-dependent PI3K/Akt/eNOS pathway by BK PC promotes VEGF secretion, hEPC survival and inhibits apoptosis, thereby improving cardiac function in vivo. The BK PC hEPC transplantation for stem cell-based therapies is a novel approach that has potential for clinical used.PLoS ONE 12/2013; 8(12):e81505. DOI:10.1371/journal.pone.0081505 · 3.53 Impact Factor
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ABSTRACT: Objective: To review studies performed in animal models that evaluated therapeutic interventions to inflammatory response and microcirculatory changes after cardiopulmonary bypass. Methods: It was used the search strategy ("Cardiopulmonary Bypass" (MeSH)) and ("Microcirculation" (MeSH) or "Inflammation" (MeSH) or "Inflammation Mediators" (MeSH)). Repeated results, human studies, non-English language articles, reviews and studies without control were excluded. Results: Blood filters, system miniaturization, specific primers regional perfusion, adequate flow and temperature and pharmacological therapies with anticoagulants, vasoactive drugs and anti-inflammatories reduced changes in microcirculation and inflammatory response. Conclusion: Demonstrated efficacy in animal models establishes a perspective for evaluating these interventions in clinical practice.Revista Brasileira de Cirurgia Cardiovascular 03/2014; 29(1):93-102. DOI:10.5935/1678-9741.20140017 · 0.63 Impact Factor