An Immunohistochemical Analysis of Tissue Thrombin Expression in the Human Atria

Ito, Keiichi; Date, Taro; Ikegami, Machiko; Hongo, Kazuhiro; Fujisaki, Masami; Katoh, Daisuke; Yoshino, Tatsuhiko; Anzawa, Ryuko; Nagoshi, Tomohisa; Yamashita, Seigo; Inada, Keiichi; Matsuo, Seiichiro; Yamane, Teiichi; Yoshimura, Michihiro

doi:10.1371/journal.pone.0065817

Cited by 32 publications

(26 citation statements)

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“…Frozen sections (4 μm) were cut using a cryostat (CM1950; Leica, Wetzlar, Germany) and either immunostained or stained with hematoxylin and eosin. Immunohistochemistry was performed as previously described [ 23 ] with rabbit polyclonal anti-SGLT1(1:100, Abcam #ab14685, Cambridge, MA, USA) [ 24 ].…”

Section: Methodsmentioning

confidence: 99%

Expression of SGLT1 in Human Hearts and Impairment of Cardiac Glucose Uptake by Phlorizin during Ischemia-Reperfusion Injury in Mice

et al. 2015

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ObjectiveSodium-glucose cotransporter 1 (SGLT1) is thought to be expressed in the heart as the dominant isoform of cardiac SGLT, although more information is required to delineate the subtypes of SGLTs in human hearts. Moreover, the functional role of SGLTs in the heart remains to be fully elucidated. We herein investigated whether SGLT1 is expressed in human hearts and whether SGLTs significantly contribute to cardiac energy metabolism during ischemia-reperfusion injury (IRI) via enhanced glucose utilization in mice.Methods and ResultsWe determined that SGLT1 was highly expressed in both human autopsied hearts and murine perfused hearts, as assessed by immunostaining and immunoblotting with membrane fractionation. To test the functional significance of the substantial expression of SGLTs in the heart, we studied the effects of a non-selective SGLT inhibitor, phlorizin, on the baseline cardiac function and its response to ischemia-reperfusion using the murine Langendorff model. Although phlorizin perfusion did not affect baseline cardiac function, its administration during IRI significantly impaired the recovery in left ventricular contractions and rate pressure product, associated with an increased infarct size, as demonstrated by triphenyltetrazolium chloride staining and creatine phosphokinase activity released into the perfusate. The onset of ischemic contracture, which indicates the initiation of ATP depletion in myocardium, was earlier with phlorizin. Consistent with this finding, there was a significant decrease in the tissue ATP content associated with reductions in glucose uptake, as well as lactate output (indicating glycolytic flux), during ischemia-reperfusion in the phlorizin-perfused hearts.ConclusionsCardiac SGLTs, possibly SGLT1 in particular, appear to provide an important protective mechanism against IRI by replenishing ATP stores in ischemic cardiac tissues via enhancing availability of glucose. The present findings provide new insight into the significant role of SGLTs in optimizing cardiac energy metabolism, at least during the acute phase of IRI.

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Section: Methodsmentioning

confidence: 99%

Expression of SGLT1 in Human Hearts and Impairment of Cardiac Glucose Uptake by Phlorizin during Ischemia-Reperfusion Injury in Mice

et al. 2015

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“…43 In a postmortem analysis, inflammatory macrophage markers and fibrosis colocalized in subendocardial atrial tissues of AF patients, consistent with an association between inflammation and fibrosis in AF. 44 …”

Section: Inflammation and Fibrosis In Afmentioning

confidence: 99%

Role of Inflammation in Atrial Fibrillation Pathophysiology and Management

Harada

Wagoner

Nattel

2015

Circ J

364

290

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Atrial fibrillation (AF) is the most common clinically relevant arrhythmia, but the methods available for treating AF and its complications (of which the most important is thrombogenesis), as well as for assessing AF risk and underlying pathophysiology, are largely limited. Emerging evidence suggests a significant role of inflammation in the pathogenesis of AF. That evidence includes elevated serum levels of inflammatory biomarkers in AF subjects, the expression of inflammatory markers in cardiac tissues of AF patients and animal models of AF, and beneficial effects of anti-inflammatory drugs in experimental AF paradigms. Inflammation is suggested to be linked to various pathological processes, such as oxidative stress, apoptosis, and fibrosis, that promote AF substrate formation. Inflammation has also been associated with endothelial dysfunction, platelet activation, and coagulation cascade activation, leading to thrombogenesis. Thus, inflammation may contribute to both the occurrence/maintenance of AF and its thromboembolic complications. Here, we review the evidence for a role of inflammation and inflammatory biomarkers in the risk management and treatment of AF. We also summarize the current knowledge of inflammation-dependent cellular and molecular mechanisms in AF pathophysiology and their potential as therapeutic targets.

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“…Thrombin activates PARs, which mediate diverse intracellular signals for cellular functions, including atrial natriuretic factor (ANF) generation and cardiac hypertrophy (Sabri et al ., ). A recent study shows that PAR1 and thrombin are up‐regulated in left atria and ventricle in patients with atrial fibrillation (Ito et al ., ). Nevertheless, little is known for the expression and role of PARs in human cardiomyocytes.…”

Section: Discussionmentioning

confidence: 97%

PAR1‐dependent COX‐2/PGE₂ production contributes to cell proliferation via EP₂ receptors in primary human cardiomyocytes

Chien

Hsieh

Ling

et al. 2014

British J Pharmacology

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BACKGROUND AND PURPOSEDifferent protease-activated receptors (PARs) activated by thrombin are involved in cardiovascular disease, via up-regulation of inflammatory proteins including COX-2. However, the mechanisms underlying thrombin-regulated COX-2 expression in human cardiomyocytes remain unclear. EXPERIMENTAL APPROACHHuman cardiomyocytes were used in the study. Thrombin-induced COX-2 protein and mRNA expression, and signalling pathways were determined by Western blot, real-time PCR and COX-2 promoter luciferase reporter assays, and pharmacological inhibitors or siRNAs. PGE2 generation and cell proliferation were also determined. KEY RESULTSThrombin-induced COX-2 protein and mRNA expression, promoter activity and PGE2 release was attenuated by the PAR1 antagonist (SCH79797) or the inhibitors of proteinase activity (PPACK), MEK1/2 (U0126), p38 MAPK (SB202190) or JNK1/2 (SP600125), and transfection with small interfering RNA (siRNA) of PAR1, p38, p42 or JNK2. These results suggested that PAR1-dependent MAPKs participate in thrombin-induced COX-2 expression in human cardiomyocytes. Moreover, thrombin stimulated phosphorylation of MAPKs, which was attenuated by PPACK and SCH79797. Furthermore, thrombin-induced COX-2 expression was blocked by the inhibitors of AP-1 (tanshinone IIA) and NF-κB (helenalin). Moreover, thrombin-stimulated phosphorylation of c-Jun/AP-1 and p65/NF-κB was attenuated by tanshinone IIA and helenalin, respectively, suggesting that thrombin induces COX-2 expression via PAR1/MAPKs/AP-1 or the NF-κB pathway. Functionally, thrombin increased human cardiomyocyte proliferation through the COX-2/PGE2 system linking to EP2 receptors, as determined by proliferating cell nuclear antigen and cyclin D1 expression. CONCLUSIONS AND IMPLICATIONSThese findings demonstrate that MAPKs-mediated activation of AP-1/NF-κB pathways is, at least in part, required for COX-2/PGE2/EP2-triggered cell proliferation in human cardiomyocytes. AbbreviationsANF, atrial natriuretic factor; PAR, protease-activated receptor; PCNA, proliferating cell nuclear antigen BJP British Journal of Pharmacology

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An Immunohistochemical Analysis of Tissue Thrombin Expression in the Human Atria

Cited by 32 publications

References 20 publications

Expression of SGLT1 in Human Hearts and Impairment of Cardiac Glucose Uptake by Phlorizin during Ischemia-Reperfusion Injury in Mice

Expression of SGLT1 in Human Hearts and Impairment of Cardiac Glucose Uptake by Phlorizin during Ischemia-Reperfusion Injury in Mice

Role of Inflammation in Atrial Fibrillation Pathophysiology and Management

PAR1‐dependent COX‐2/PGE₂ production contributes to cell proliferation via EP₂ receptors in primary human cardiomyocytes

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An Immunohistochemical Analysis of Tissue Thrombin Expression in the Human Atria

Cited by 32 publications

References 20 publications

Expression of SGLT1 in Human Hearts and Impairment of Cardiac Glucose Uptake by Phlorizin during Ischemia-Reperfusion Injury in Mice

Expression of SGLT1 in Human Hearts and Impairment of Cardiac Glucose Uptake by Phlorizin during Ischemia-Reperfusion Injury in Mice

Role of Inflammation in Atrial Fibrillation Pathophysiology and Management

PAR1‐dependent COX‐2/PGE2 production contributes to cell proliferation via EP2 receptors in primary human cardiomyocytes

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PAR1‐dependent COX‐2/PGE₂ production contributes to cell proliferation via EP₂ receptors in primary human cardiomyocytes