No Pain, No Gain

Bolli, Roberto; Abdel‐Latif, Ahmed

doi:10.1161/circulationaha.105.581827

Cited by 18 publications

(13 citation statements)

References 27 publications

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“…In addition, the results from the present study are not in complete agreement with a report that employed mice that had a targeted deletion of the TRPV1 (vanilloid receptor 1) gene (4,37). In this study, isolated perfused heart preparations from TRPV1 KO and WT mice were subjected to 40 min of ischemia followed by 30 min of reperfusion.…”

Section: Discussioncontrasting

confidence: 78%

“…Under conditions of myocardial ischemia-reperfusion (I/R), the unmyelinated Cfiber and thinly myelinated A␦-fiber nerves play an afferent role, resulting in pain perception and a possible efferent cardioprotective role that is mediated through the release of CGRP and/or substance P (25, 37). This release of these sensory neuropeptides appears to be caused by activation of the vanilloid receptor 1, which is also known as transient receptor potential vanilloid type 1 (TRPV1), by the I/R-evoked production of protons, bradykinin, and other stimuli (4,29).A number of in vivo and in vitro studies indicate that sensory nerves, through CGRP, can significantly attenuate cardiac I/R injury and also play a role in cardiac preconditioning (both early and late) and remote preconditioning …”

mentioning

confidence: 99%

“…However, not all of the reports are in agreement, and the mechanisms are still unclear. In addition, other investigators have reported that substance P release from cardiac sensory nerves can act in a paracrine manner to reduce I/R injury (4,10,35,37). In light of the aforementioned studies, and given our extensive experience with the ␣-CGRP knockout (KO) mouse, notably studies demonstrating that ␣-CGRP possesses significant protective activity against hypertension-induced heart and kidney damage, with inhibition of oxidative stress being one of the underlying mechanisms (5,31), it was logical to use this genetic model to assess the role of ␣-CGRP in cardiac I/R injury.…”

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confidence: 99%

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Deletion of the mouse α-calcitonin gene-related peptide gene increases the vulnerability of the heart to ischemia-reperfusion injury

Huang¹,

Karve²,

Shah³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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Huang R, Karve A, Shah I, Bowers MC, DiPette DJ, Supowit SC, Abela GS. Deletion of the mouse ␣-calcitonin gene-related peptide gene increases the vulnerability of the heart to ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol 294: H1291-H1297, 2008. First published January 11, 2008 doi:10.1152/ajpheart.00749.2007.-Calcitonin gene-related peptide (CGRP), a potent vasodilator released from capsaicin-sensitive C-fiber and A␦-fiber sensory nerves, has been suggested to play a beneficial role in myocardial ischemia-reperfusion (I/R) injury. Because most previous studies showing a cardioprotective role of CGRP employed pharmacological experiments, the purpose of this study was to utilize a genetic approach by using mice with a targeted deletion of the ␣-CGRP gene to determine whether this neuropeptide had a modulatory function on the severity of I/R injury. To accomplish this goal, isolated, perfused hearts from ␣-CGRP knockout (KO) and wild-type (WT) mice were subjected to 30 min of ischemia followed by 5, 15, and 30 min of reperfusion. Cardiac functional parameters, including coronary flow rates, left ventricular developed pressure, maximum rates of pressure development, and left ventricular end-diastolic pressure, were measured before and after I/R injury, as were levels of creatine kinase, to assess myocardial damage, and malonaldehyde, to assess oxidative stress. Following I/R injury, cardiac performance was significantly reduced in the hearts from the ␣-CGRP KO mice compared with their WT counterparts. The marked reduction in myocardial function in the ␣-CGRP KO hearts compared with WT hearts after I/R injury was associated with a significant elevation in creatine kinase release into the perfusates and malonaldehyde production in the cardiac tissue. Therefore, these data indicate that, in this in vitro setting, deletion of ␣-CGRP makes the heart more vulnerable to I/R injury, possibly due, at least in part, to increased oxidative stress. genetically modified mice; cardiac; isolated perfused heart preparations; sensory nervous system CALCITONIN GENE-RELATED PEPTIDE (CGRP), a 37-amino acid neuropeptide, is derived from the tissue-specific splicing of the primary transcript of the calcitonin/␣-CGRP gene (6,8,13,38). Whereas calcitonin is produced mainly in the C cells of the thyroid, CGRP synthesis is limited almost exclusively to specific regions of the central and peripheral nervous systems. There is a second CGRP gene (␤-CGRP) that does not produce calcitonin, which is also synthesized primarily in neuronal tissues. The two CGRP genes, ␣ and ␤ in the rat and I and II in humans, differ in their protein sequences by one and three amino acids, respectively, and the biological activities of the two peptides are quite similar in most vascular beds. However, ␣-CGRP is by far the predominant product in dorsal root ganglia sensory neurons and appears to be the CGRP gene product that has markedly greater activity in the regulation of cardiovascular function (5, 11, 31).Immunoreactive CGRP and its receptor are...

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Section: Discussioncontrasting

confidence: 78%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Deletion of the mouse α-calcitonin gene-related peptide gene increases the vulnerability of the heart to ischemia-reperfusion injury

Huang¹,

Karve²,

Shah³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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“…18 Recent studies have shown that TRPV1 contributes to the beneficial effects of preconditioning the heart against ischemiareperfusion injury by triggering the release of substance P and/or calcitonin gene-related peptide; it also modulates inflammatory and early remodeling processes to prevent cardiac functional deterioration after myocardial infarction. 7, 19 Modest pH shifts (7.4-6.7) during early myocardial ischemia, can induce sustained activation of ASIC3, 12 whereas lower pH is needed for the activation of TRPV1.…”

Section: Discussionmentioning

confidence: 99%

“…These results are in agreement with a recent editorial, "No pain, no gain: the useful function of angina". 18 We propose that both ASIC3 and TRPV1 are important in ischemic cardiac sensing. ASIC3 is activated first and works as an alarm in early myocardial ischemia, whereas TRPV1 is triggered later during tissue acidosis and works as damage control to limit inflammation/remodeling and restore the left ventricular function.…”

Section: Cheng Cf Et Almentioning

confidence: 98%

Acid-Sensing Ion Channel 3, But Not Capsaicin Receptor TRPV1, Plays a Protective Role in Isoproterenol-Induced Myocardial Ischemia in Mice

Cheng

Chen

Cheng

et al. 2011

Circ J

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Background: Cardiac angina is the hallmark of myocardial ischemia, but the role of the cardiac sensory nerve has received relatively little attention. Recently, both acid-sensing ion channel 3 (ASIC3) and capsaicin receptor (TRPV1) have been suggested as important mediators in sensing myocardial ischemia. However, studies comparing the physiological roles of ASIC3 and TRPV1 in the neuronal - cardiac sensing circuits in vivo are lacking. Methods and Results:Isoproterenol (1.5 mg/kg, intraperitoneally) was used to induce transient myocardial ischemia in Asic3 +/+ and Asic3 -/-mice and a radio-telemetry system was used for electrocardiography with mice in a conscious state. Isoproterenol-induced myocardial ischemia was first demonstrated with ST-segment depression and further confirmed by hypoxia-mediated chemical reactions in cardiac tissue. Mice lacking Asic3 showed prolonged duration of ST-segment depression compared with Asic3 +/+ mice (44.3±3.1 vs. 31.7±2.9 min; P<0.05). Although ischemia was transient, severe cardiac fibrosis was found in Asic3 -/-but not in Asic3 +/+ mice littermates. In contrast, isoproterenol-injected Trpv1 +/+ and Trpv1 -/-mice showed no difference in duration of ST-segment depression and, surprisingly, deletion of Trpv1 did not aggravate cardiac fibrosis.Conclusions: An isoproterenol-induced myocardial ischemia model mimicking clinical conditions of early cardiac angina was used to demonstrate that ASIC3 but not TRPV1 plays a protective role in sensing myocardial ischemia. (Circ J 2011; 75: 174 - 178)

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4,5‐Di‐O‐Caffeoylquinic Acid from Ligularia fischeri Suppresses Inflammatory Responses Through TRPV1 Activation

Kim

Park

et al. 2017

Phytotherapy Research

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Ligularia fischeri (Ledeb.) Turcz., a perennial plant native to northeastern Asia, has long been used as folk remedies for the alleviation of inflammatory symptoms. We investigated whether the extract of L. fischeri (LFEx) and caffeoylquinic acid (CQA) derivatives, the pharmacologically active ingredients identified from L. fischeri, regulate inflammation via a transient receptor potential vanilloid 1 (TRPV1)-mediated pathway. Changes in intracellular Ca levels to the LFEx and trans-5-O-CQA, 3,4-di-O-CQA, 3,5-di-O-CQA, and 4,5-di-O-CQA were monitored in TRPV1-expressing human embryonic kidney cell HEK 293T. LFEx and 4,5-di-O-CQA (EC = 69.34 ± 1.12 μM) activated TRPV1, and these activations were significantly inhibited by ruthenium red, a general blocker of TRP channels, and capsazepine, a specific antagonist of TRPV1. 4,5-Di-O-CQA has been determined having antiinflammatory effect under hypoxic conditions by detecting the expression of cyclooxygenase-2 (COX-2), a representative inflammatory marker, and cellular migration in human pulmonary epithelial A549 cells. 4,5-Di-O-CQA suppressed COX-2 expression and cell migration, and this inhibition was countered by co-treatment with capsazepine. This study provides evidence that L. fischeri is selective to inflammatory responses via a TRPV1-mediated pathway, and 4,5-di-O-CQA might play a key role to create these effects. Copyright © 2017 John Wiley & Sons, Ltd.

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No Pain, No Gain

Cited by 18 publications

References 27 publications

Deletion of the mouse α-calcitonin gene-related peptide gene increases the vulnerability of the heart to ischemia-reperfusion injury

Deletion of the mouse α-calcitonin gene-related peptide gene increases the vulnerability of the heart to ischemia-reperfusion injury

Acid-Sensing Ion Channel 3, But Not Capsaicin Receptor TRPV1, Plays a Protective Role in Isoproterenol-Induced Myocardial Ischemia in Mice

4,5‐Di‐O‐Caffeoylquinic Acid from Ligularia fischeri Suppresses Inflammatory Responses Through TRPV1 Activation

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