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

2008 ◽  
Vol 294 (3) ◽  
pp. H1291-H1297 ◽  
Author(s):  
Ruiping Huang ◽  
Amrita Karve ◽  
Ibrahim Shah ◽  
Mark C. Bowers ◽  
Donald J. DiPette ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Creatine Kinase ◽  
Ischemia Reperfusion Injury ◽  
Diastolic Pressure ◽  
Ischemia Reperfusion ◽  
Calcitonin Gene Related Peptide ◽  
Left Ventricular ◽  
Sensory Nerves ◽  
Related Peptide ◽  
Calcitonin Gene

Calcitonin gene-related peptide (CGRP), a potent vasodilator released from capsaicin-sensitive C-fiber and Aδ-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 α-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 α-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 α-CGRP KO mice compared with their WT counterparts. The marked reduction in myocardial function in the α-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 α-CGRP makes the heart more vulnerable to I/R injury, possibly due, at least in part, to increased oxidative stress.

scholarly journals Cardioprotective Effects of PPARβ/δ Activation against Ischemia/Reperfusion Injury in Rat Heart Are Associated with ALDH2 Upregulation, Amelioration of Oxidative Stress and Preservation of Mitochondrial Energy Production

2021 ◽  
Vol 22 (12) ◽  
pp. 6399
Author(s):  
Ioanna Papatheodorou ◽  
Eleftheria Galatou ◽  
Georgios-Dimitrios Panagiotidis ◽  
Táňa Ravingerová ◽  
Antigone Lazou
Keyword(s):  
Oxidative Stress ◽  
Mrna Expression ◽  
Energy Production ◽  
Citrate Synthase ◽  
Ischemia Reperfusion Injury ◽  
Ex Vivo ◽  
Uncoupling Protein ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Isocitrate Dehydrogenase 2

Accumulating evidence support the cardioprotective properties of the nuclear receptor peroxisome proliferator activated receptor β/δ (PPARβ/δ); however, the underlying mechanisms are not yet fully elucidated. The aim of the study was to further investigate the mechanisms underlying PPARβ/δ-mediated cardioprotection in the setting of myocardial ischemia/reperfusion (I/R). For this purpose, rats were treated with PPARβ/δ agonist GW0742 and/or antagonist GSK0660 in vivo and hearts were subjected to ex vivo global ischemia followed by reperfusion. PPARβ/δ activation improved left ventricular developed pressure recovery, reduced infarct size (IS) and incidence of reperfusion-induced ventricular arrhythmias while it also up-regulated superoxide dismutase 2, catalase and uncoupling protein 3 resulting in attenuation of oxidative stress as evidenced by the reduction in 4-hydroxy-2-nonenal protein adducts and protein carbonyl formation. PPARβ/δ activation also increased both mRNA expression and enzymatic activity of aldehyde dehydrogenase 2 (ALDH2); inhibition of ALDH2 abrogated the IS limiting effect of PPARβ/δ activation. Furthermore, upregulation of PGC-1α and isocitrate dehydrogenase 2 mRNA expression, increased citrate synthase activity as well as mitochondrial ATP content indicated improvement in mitochondrial content and energy production. These data provide new mechanistic insight into the cardioprotective properties of PPARβ/δ in I/R pointing to ALDH2 as a direct downstream target and suggesting that PPARβ/δ activation alleviates myocardial I/R injury through coordinated stimulation of the antioxidant defense of the heart and preservation of mitochondrial function.

Role of oxidative stress in alterations of mitochondrial function in ischemic-reperfused hearts

2007 ◽  
Vol 292 (4) ◽  
pp. H1986-H1994 ◽  
Author(s):  
Zhanna Makazan ◽  
Harjot K. Saini ◽  
Naranjan S. Dhalla
Keyword(s):  
Oxidative Stress ◽  
Oxidative Phosphorylation ◽  
Mitochondrial Function ◽  
Mitochondrial Respiration ◽  
Diastolic Pressure ◽  
Ischemia Reperfusion ◽  
Respiratory Control ◽  
Left Ventricular ◽  
Cardiac Performance ◽  
Developed Pressure

To study the mechanisms of mitochondrial dysfunction due to ischemia-reperfusion (I/R) injury, rat hearts were subjected to 20 or 30 min of global ischemia followed by 30 min of reperfusion. After recording both left ventricular developed pressure (LVDP) and end-diastolic pressure (LVEDP) to monitor the status of cardiac performance, mitochondria from these hearts were isolated to determine respiratory and oxidative phosphorylation activities. Although hearts subjected to 20 min of ischemia failed to generate LVDP and showed a marked increase in LVEDP, no changes in mitochondrial respiration and phosphorylation were observed. Reperfusion of 20-min ischemic hearts depressed mitochondrial function significantly but recovered LVDP completely and lowered the elevated LVEDP. On the other hand, depressed LVDP and elevated LVEDP in 30-min ischemic hearts were associated with depressions in both mitochondrial respiration and oxidative phosphorylation. Reperfusion of 30-min ischemic hearts elevated LVEDP, attenuated LVDP, and decreased mitochondrial state 3 and uncoupled respiration, respiratory control index, ADP-to-O ratio, as well as oxidative phosphorylation rate. Alterations of cardiac performance and mitochondrial function in I/R hearts were attenuated or prevented by pretreatment with oxyradical scavenging mixture (superoxide dismutase and catalase) or antioxidants [ N-acetyl-l-cysteine or N-(2-mercaptopropionyl)-glycine]. Furthermore, alterations in cardiac performance and mitochondrial function due to I/R were simulated by an oxyradical-generating system (xanthine plus xanthine oxidase) and an oxidant (H2O2) either upon perfusing the heart or upon incubation with mitochondria. These results support the view that oxidative stress plays an important role in inducing changes in cardiac performance and mitochondrial function due to I/R.

Human calcitonin gene related peptide: a potent endogenous vasodilator in man

1986 ◽  
Vol 70 (4) ◽  
pp. 389-393 ◽  
Author(s):  
A. D. Struthers ◽  
M. J. Brown ◽  
D. W. R. Macdonald ◽  
J. L. Beacham ◽  
J. C. Stevenson ◽  
...  
Keyword(s):  
Diastolic Pressure ◽  
Normal Subjects ◽  
Calcitonin Gene Related Peptide ◽  
Plasma Calcium ◽  
Human Calcitonin ◽  
High Concentration ◽  
Plasma Adrenaline ◽  
Related Peptide ◽  
Calcitonin Gene ◽  
Perivascular Nerves

1. In addition to calcitonin and katacalcin, it is now known that the human calcitonin gene encodes a novel peptide called calcitonin gene related peptide (CGRP). In experimental animals, CGRP produces vasodilatation and complex changes in plasma calcium. 2. We have now assessed its biological activity in man by infusing human CGRP (hCGRP) into six normal volunteers. hCGRP (545 pmol/min) caused the diastolic pressure to fall from 64 ± 5 to 55 ± 7mmHg (P < 0.05), the heart rate to increase from 61 ± 7 to 87 ± 5 beats/min (P < 0.05) and the skin temperature to increase from 33.7 ± 0.9 to 34.9 ± 0.5°C. Plasma noradrenaline increased from 481 ± 126 to 835 ± 65 pg/ml (P < 0.05) and plasma adrenaline from 57 ± 17 to 82 ± 12 pg/ml (P < 0.05). There were no significant changes in the albumin-corrected plasma calcium. 3. hCGRP is thus a potent endogenous vasodilator in man and is in fact more potent than any other known vasodilator. Together with the observations that CGRP circulates in normal subjects at relatively high concentration (approximately 25 pmol/l) and that CGRP is present in perivascular nerves, this study suggests a possible role for CGRP in controlling peripheral vascular tone in man.

Effect of ω-Conotoxin GVIA and ω-Agatoxin IVA on the Capsaicin-Sensitive Calcitonin Gene-Related Peptide Release and Autoregulatory Vasodilation in Rat Pial Arteries

1999 ◽  
Vol 19 (1) ◽  
pp. 53-60 ◽  
Author(s):  
Ki Whan Hong ◽  
Chi Dae Kim ◽  
Byung Yong Rhim ◽  
Won Suk Lee
Keyword(s):  
Calcitonin Gene Related Peptide ◽  
Sensory Nerves ◽  
Channel Blockers ◽  
Pial Arteries ◽  
Cranial Window ◽  
Related Peptide ◽  
Calcitonin Gene ◽  
Peptide Release ◽  
Acute Hypotension ◽  
P Type

This study assesses the effect of neuronal voltage-sensitive Ca2+ channel blockers, ω-conotoxin GVIA (CTX), and ω-agatoxin IVA (AgTX) on the vasodilation and release of calcitonin gene-related peptide (CGRP), both of which were induced by either application of capsaicin or acute stepwise hypotension. Changes in pial arterial diameter were determined directly through a closed cranial window. The vasodilation of pial artery induced by either CGRP (0.1 μmol/L) or capsaicin (0.3 μmol/L) was significantly inhibited by CGRP8–37 (0.1 μmol/L) ( P < 0.05 and P < 0.05, respectively). The autoregulatory vasodilation to acute stepwise hypotension was severely attenuated by pretreatment with either CTX or AgTX. When the hypotension was kept for 2, 4, and 10 minutes, the releasable CGRP-like immunoreactivity (CGRP-LI) level (vehicle, 13.4 ± 1.5 fmol/mm2/30 min) by 10 μmol/L capsaicin from the isolated pial arteries was significantly reduced in the 4- and 10-minute hypotension groups (11.3 ± 1.2 fmol/mm2/30 min, P < 0.05, and 11.1 ± 1.5 fmol/mm2/30 min, P < 0.05, respectively), but not in 2-min group. Moreover, the CGRP-LI level released by 10 μmol/L capsaicin (13.7 ± 0.9 fmol/mm2/30 min) also was significantly depressed by pretreatment with 1 μmol/L CTX to 10.4 ± 1.0 fmol/mm2/30 min ( P < 0.01) and with 0.1 μmol/L AgTX to 8.7 (1.7 fmol/mm2/30 min ( P < 0.001), as well as by pretreatment with 10 μmol/L capsaicin (6.0 ± 1.6 fmol/mm2/30 min, P < 0.001). These results suggest that the neuronal N- and P-type voltage-sensitive Ca2+ channels are implicated in the release of CGRP from capsaicin-sensitive perivascular sensory nerves in response to acute hypotension, and that the released CGRP may contribute to the autoregulatory vasodilation in the cerebral microcirculation.

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