RETRACTED ARTICLE: Postconditioning promotes the cardiac repair through balancing collagen degradation and synthesis after myocardial infarction in rats
Cardiovascular Research Laboratory, Mercer University School of Medicine, Savannah, GA, USA. Archiv für Kreislaufforschung
(Impact Factor: 5.41).
01/2013; 108(1):318. DOI: 10.1007/s00395-012-0318-9
Postconditioning (Postcon) reduces infarct size. However, its role in modulation of cardiac repair after infarction is uncertain. This study tested the hypothesis that Postcon inhibits adverse cardiac repair by reducing degradation of extracellular matrix (ECM) and synthesis of collagens via modulating matrix metalloproteinase (MMP) activity and transforming growth factor (TGF) β1/Smad signaling pathway. Sprague-Dawley rats were subjected to 45 min ischemia followed by 3 h, 7 or 42 days of reperfusion, respectively. In acute studies, four cycles of 10/10 s Postcon significantly reduced infarct size, which was blocked by administration of a mitochondrial K(ATP) channel blocker, 5-hydroxydecanoate (5-HD) at reperfusion. In chronic studies, Postcon inhibited MMP activity and preserved ECM from degradation as evidenced by reduced extent of collagen-rich scar and increased mass of viable myocardium. Along with a reduction in collagen synthesis and fibrosis, Postcon significantly down-regulated expression of TGFβ1 and phospho-Smad2/3, and up-regulated Smad7 as compared to the control, consistent with a reduction in the population of α-smooth muscle actin expressing myofibroblasts within the infarcted myocardium. At 42 days of reperfusion, echocardiography showed significant improvements in left ventricular end-diastolic volume and ejection fraction. The wall thickness of the infarcted middle anterior septum in the Postcon was also significantly greater than that in the control. The beneficial effects of Postcon on cardiac repair were comparable to preconditioning and still evident after a blockade with 5-HD. These data suggest that Postcon is effective to promote cardiac repair and preserve cardiac function; protection is potentially mediated by inhibiting ECM degradation and collagen synthesis.
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Available from: Peter Whittaker
- "For example, remote conditioning failed to enhance healing, as indicated by changes in tissue hydroxyproline content, after bowel anastomosis surgery in rats (Colak et al. 2007; Holzner et al. 2011). Conversely, post-conditioning was reported to exert a favorable effect on repair at one and six weeks after myocardial infarction in rats by reduction of the area occupied by collagen and an attenuation in expression of collagen types I and III (Wang et al. 2013). However, histological assessment of collagen content was performed with trichrome staining which is known to underestimate collagen content (Whittaker et al. 1994). "
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ABSTRACT: Thousands of articles have been published on the topic of ischemic conditioning. Nevertheless, relatively little attention has been given to assessment of conditioning's dose-response characteristics. Specifically, the consequences of multiple conditioning epi-sodes, what we will term "hyperconditioning", have seldom been examined. We propose that hyperconditioning warrants investigation because it; (1) may be of clinical impor-tance, (2) could provide insight into conditioning mechanisms, and (3) might result in development of novel models of human disease. The prevalence of angina pectoris and intermittent claudication is sufficiently high and the potential for daily ischemia-reperfu-sion episodes sufficiently large that hyperconditioning is a clinically relevant phenomenon. In basic science, attenuation of conditioning-mediated infarct size reduction found in some studies after hyperconditioning offers a possible means to facilitate further dis-cernment of cardioprotective signaling pathways. Moreover, hyperconditioning's impact extends beyond cytoprotection to tissue structural elements. Several studies demonstrate that hyperconditioning produces collagen injury (primarily fiber breakage). Such struc-tural impairment could have adverse clinical consequences; however, in laboratory stud-ies, selective collagen damage could provide the basis for models of cardiac rupture and dilated cardiomyopathy. Accordingly, we propose that hyperconditioning represents the dark, but potentially illuminating, side of ischemic conditioning -a paradigm that merits attention and prospective evaluation.
Available from: Michael Hamblin
- "(Kawano et al, 2012) Kinin receptors Down-regulates kinin receptor expression in neutrophils of patients undergoing heart surgery . (Saxena et al, 2013) Downregulates kinin receptors mRNA expression in the subplantar muscle of rat paw (Bortone et al, 2008) Ion channels K(+) inward rectifier subunits of the 6.2 isotype (Kir6.2) required for cardioprotection (Wojtovich et al, 2013) Increased Ca2+ in oral tissue cells via TRPC1 ion channels (Chellini et al, 2010) Cyclic AMP/CREB CREB phosphorylation contributes to triggering preconditioning in rat heart (Marais et al, 2008) Promotes the proliferation and osteogenic differentiation of human periodontal ligament cells via cyclic AMP (Wu et al, 2013) VEGF Overexpression of VEGF protects intrahepatic cholangiocytes after liver transplantation in rats (Zhou et al, 2010) Increases angiogenesis in a model of ischemic skin flap in rats mediated by VEGF, HIF-1α and MMP-2 (Cury et al, 2013) Hypoxia-inducible factor 1 HIF-1 activates IL10 gene transcription and is required for remote ischemic preconditioning in mice heart (Cai et al, 2013; Kalakech et al, 2013) Reduces the overexpressions of HIF-1α, TNF-α, and IL-1β, and increases the amounts of VEGF, NGF, and S100 proteins in rats with chronic constriction injury (Hsieh et al, 2012) TFG-beta Downregulated TGFβ1 but upregulated smad7 in cardiac infarcts (Wang et al, 2013) Increase in proliferation of vascular endothelial cells and decrease in VEGF and TGF-beta secretion. (Szymanska et al, 2013) …continued mechanisms is hypothesized to be at the level of mitochondria (Dirnagl and Meisel, 2008). "
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ABSTRACT: Pre-conditioning by ischemia, hyperthermia, hypothermia, hyperbaric oxygen (and numerous other modalities) is a rapidly growing area of investigation that is used in pathological conditions where tissue damage may be expected. The damage caused by surgery, heart attack, or stroke can be mitigated by pre-treating the local or distant tissue with low levels of a stress-inducing stimulus, that can induce a protective response against subsequent major damage. Low-level laser (light) therapy (LLLT) has been used for nearly 50 years to enhance tissue healing and to relieve pain, inflammation and swelling. The photons are absorbed in cytochrome(c) oxidase (unit four in the mitochondrial respiratory chain), and this enzyme activation increases electron transport, respiration, oxygen consumption and ATP production. A complex signaling cascade is initiated leading to activation of transcription factors and up- and down-regulation of numerous genes. Recently it has become apparent that LLLT can also be effective if delivered to normal cells or tissue before the actual insult or trauma, in a pre-conditioning mode. Muscles are protected, nerves feel less pain, and LLLT can protect against a subsequent heart attack. These examples point the way to wider use of LLLT as a pre-conditioning modality to prevent pain and increase healing after surgical/medical procedures and possibly to increase athletic performance.
- "It is known that mammalian cardiomyocytes are terminal and non-proliferative cells. The myocardial injury is generally repaired by fibroblast proliferation and ECM accumulation in adults (16). This massive ECM accumulation leads to cardiac fibrosis, dysfunction and even failure (17). "
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ABSTRACT: Hypoxia is a primary mediator for cell survival, and has been reported to inhibit cardiomyocyte proliferation in fetal and neonatal hearts. CyclinA2 is a key regulator of cell proliferation. Whether CyclinA2 affects cardiomyocyte proliferation in hypoxic conditions remains unexamined. This study was designed to investigate the roles of CyclinA2 expression on hypoxia-impaired cardiomyocyte proliferation. Cardiomyocytes were isolated from neonatal rats and randomly separated into six groups: Control, hypoxia, enhanced green fluorescent protein (EGFP)-Adv, EGFP-Ccna2, EGFP-Adv + hypoxia and EGFP-Ccna2 + hypoxia. The cells in the control group were cultured in a general cell incubator; the cells in the hypoxia group were placed in a hypoxic chamber for 12 h; the cells in the EGFP-Adv and EGFP-Ccna2 groups were separately transfected with EGFP-adenovirus capsids or EGFP-adenovirus capsids with CyclinA2 cDNA for 18 h, and then placed in a general incubator for an additional 12 h; the cells in the EGFP-Adv + hypoxia and EGFP-Ccna2 + hypoxia groups were separately transfected with EGFP-adenovirus capsids or EGFP-adenovirus capsids with CyclinA2 cDNA for 18 h, and then placed in a hypoxia chamber for an additional 12 h. CyclinA2 expression was measured using immunochemical staining and western blot analysis, and cardiomyocyte proliferation was measured using the cell counting kit 8. GFP fluorescence indicated a high transfection efficiency (>80%), and immunochemical staining showed that CyclinA2 was mainly distributed in the nucleus. CyclinA2 expression was downregulated following exposure to hypoxia for 12 h. Cardiomyocyte proliferation was also significantly decreased following exposure to hypoxia for 12 h. However, compared with the EGFP-Adv group, CyclinA2 expression and cardiomyocyte proliferation was markedly increased in the EGFP-Ccna2 group. Furthermore, compared with the EGFP-Adv + hypoxia group, CyclinA2 expression and cell proliferation were markedly increased in the EGFP-Ccna2 + hypoxia group. These findings indicate that CyclinA2 upregulation improves cardiomyocyte proliferation in hypoxic conditions.
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