scholarly journals Protease-activated receptor 2-mediated protection of myocardial ischemia-reperfusion injury: role of transient receptor potential vanilloid receptors

2009 ◽  
Vol 297 (6) ◽  
pp. R1681-R1690 ◽  
Author(s):  
Beihua Zhong ◽  
Donna H. Wang
Keyword(s):  
Transient Receptor Potential ◽  
Diastolic Pressure ◽  
Ischemia Reperfusion ◽  
Left Ventricular Pressure ◽  
Receptor Potential ◽  
Left Ventricular ◽  
Transient Receptor Potential Vanilloid ◽  
Transient Receptor ◽  
Myocardial Ischemia Reperfusion ◽  
Developed Pressure

Activation of the protease-activated receptor 2 (PAR2) or the transient receptor potential vanilloid type 1 (TRPV1) channels expressed in cardiac sensory afferents containing calcitonin gene-related peptide (CGRP) and/or substance P (SP) has been proposed to play a protective role in myocardial ischemia-reperfusion (I/R) injury. However, the interaction between PAR2 and TRPV1 is largely unknown. Using gene-targeted TRPV1-null mutant (TRPV1−/−) or wild-type (WT) mice, we test the hypothesis that TRPV1 contributes to PAR2-mediated cardiac protection via increasing the release of CGRP and SP. Immunofluorescence labeling showed that TRPV1 coexpressed with PAR2, PKC-ε, or PKAc in cardiomyocytes, cardiac blood vessels, and perivascular nerves in WT but not TRPV1−/− hearts. WT or TRPV1−/− hearts were Langendorff perfused with the selective PAR2 agonist, SLIGRL, in the presence or absence of various antagonists, followed by 35 min of global ischemia and 40 min of reperfusion (I/R). The recovery rate of coronary flow, the maximum rate of left ventricular pressure development, left ventricular end-diastolic pressure, and left ventricular developed pressure were evaluated after I/R. SLIGRL improved the recovery of hemodynamic parameters, decreased lactate dehydrogenase release, and reduced the infarct size in both WT and TRPV1−/− hearts ( P < 0.05). The protection of SLIGRL was significantly surpassed for WT compared with TRPV1−/− hearts ( P < 0.05). CGRP8–37, a selective CGRP receptor antagonist, RP67580, a selective neurokinin-1 receptor antagonist, PKC-ε V1–2, a selective PKC-ε inhibitor, or H-89, a selective PKA inhibitor, abolished SLIGRL protection by inhibiting the recovery of the rate of coronary flow, maximum rate of left ventricular pressure development, and left ventricular developed pressure, and increasing left ventricular end-diastolic pressure in WT but not TRPV1−/− hearts. Radioimmunoassay showed that SLIGRL increased the release of CGRP and SP in WT but not TRPV1−/− hearts ( P < 0.05), which were prevented by PKC-ε V1–2 and H-89. Thus our data show that PAR2 activation improves cardiac recovery after I/R injury in WT and TRPV1−/− hearts, with a greater effect in the former, suggesting that PAR2-mediated protection is TRPV1 dependent and independent, and that dysfunctional TRPV1 impairs PAR2 action. PAR2 activation of the PKC-ε or PKA pathway stimulates or sensitizes TRPV1 in WT hearts, leading to the release of CGRP and SP that contribute, at least in part, to PAR2-induced cardiac protection against I/R injury.

scholarly journals Blockade of Transient Receptor Potential Vanilloid 4 Enhances Antioxidation after Myocardial Ischemia/Reperfusion

2019 ◽  
Vol 2019 ◽  
pp. 1-17 ◽  
Author(s):  
Qiongfeng Wu ◽  
Kai Lu ◽  
Zhaoyang Zhao ◽  
Binbin Wang ◽  
Huixia Liu ◽  
...  
Keyword(s):  
Myocardial Ischemia ◽  
Transient Receptor Potential ◽  
Ischemia Reperfusion ◽  
Receptor Potential ◽  
Nuclear Accumulation ◽  
Transient Receptor Potential Vanilloid ◽  
Antioxidative Stress ◽  
Transient Receptor ◽  
Myocardial Ischemia Reperfusion

Antioxidative stress provides a cardioprotective effect during myocardial ischemia/reperfusion (I/R). Previous research has demonstrated that the blockade of transient receptor potential vanilloid 4 (TRPV4) attenuates myocardial I/R injury. However, the underlying mechanism remains unclear. The current study is aimed at investigating the antioxidative activity of TRPV4 inhibition and elucidating the underlying mechanisms in vitro and ex vivo. We found that the inhibiting TRPV4 by the selective TRPV4 blocker HC-067047 or specific TRPV4-siRNA significantly reduces reactive oxygen species (ROS) and methane dicarboxylic aldehyde (MDA) levels in H9C2 cells exposed to hypoxia/reoxygenation (H/R). Meanwhile, the activity of antioxidative enzymes, particularly superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), is enhanced. Furthermore, after H/R, HC-067047 treatment increases the expression of P-Akt and the translocation of nuclear factor E2-related factor 2 (Nrf2) and related antioxidant response element (ARE) mainly including SOD, GSH-Px, and catalase (CAT). LY294002, an Akt inhibitor, suppresses HC-067047 and specific TRPV4-siRNA-induced Nrf2 expression and its nuclear accumulation. Nrf2 siRNA attenuates HC-067047 and specific TRPV4-siRNA-induced ARE expression. In addition, treatment with LY294002 or Nrf2 siRNA significantly attenuates the antioxidant and anti-injury effects of HC-067047 in vitro. Finally, in experiments on isolated rat hearts, we confirmed the antioxidative stress roles of TRPV4 inhibition during myocardial I/R and the application of exogenous H2O2. In conclusion, the inhibition of TRPV4 exerts cardioprotective effects through enhancing antioxidative enzyme activity and expressions via the Akt/Nrf2/ARE pathway.

scholarly journals N-oleoyldopamine, a novel endogenous capsaicin-like lipid, protects the heart against ischemia-reperfusion injury via activation of TRPV1

2008 ◽  
Vol 295 (2) ◽  
pp. H728-H735 ◽  
Author(s):  
Beihua Zhong ◽  
Donna H. Wang
Keyword(s):  
Protective Effect ◽  
Receptor Antagonist ◽  
Transient Receptor Potential ◽  
Ischemia Reperfusion Injury ◽  
Diastolic Pressure ◽  
Ischemia Reperfusion ◽  
Receptor Potential ◽  
Left Ventricular ◽  
Mammalian Brain ◽  
Transient Receptor Potential Vanilloid

N-oleoyldopamine (OLDA), a bioactive lipid originally found in the mammalian brain, is an endovanilloid that selectively activates the transient receptor potential vanilloid type 1 (TRPV1) channel. This study tests the hypothesis that OLDA protects the heart against ischemia and reperfusion (I/R) injury via activation of the TRPV1 in wild-type (WT) but not in gene-targeted TRPV1-null mutant (TRPV1−/−) mice. Hearts of WT or TRPV1−/− mice were Langendorffly perfused with OLDA (2 × 10−9 M) in the presence or absence of CGRP8–37 (1 × 10−6 M), a selective calcitonin gene-related peptide (CGRP) receptor antagonist; RP-67580 (1 × 10−6 M), a selective neurokinin-1 receptor antagonist; chelerythrine (5 × 10−6 M), a selective protein kinase C (PKC) antagonist; or tetrabutylammonium (TBA, 5 × 10−4 M), a nonselective K+ channel antagonist, followed by 35 min of global ischemia and 40 min of reperfusion (I/R). Left ventricular end-diastolic pressure (LVEDP), left ventricular developed pressure (LVDP), coronary flow (CF), and left ventricular peak positive dP/d t (+dP/d t) were evaluated after I/R. OLDA improved recovery of cardiac function after I/R in WT but not TRPV1−/− hearts by increasing LVDP, CF, and +dP/d t and by decreasing LVEDP. CGRP8–37, RP-67580, chelerythrine, or TBA abolished the protective effect of OLDA in WT hearts. Radioimmunoassay showed that the release of substance P (SP) and CGRP after OLDA treatment was higher in WT than in TRPV1−/− hearts, which was blocked by chelerythrine or TBA. Thus OLDA exerts a cardiac protective effect during I/R injury in WT hearts via CGRP and SP release, which is abolished by PKC or K+ channel antagonists. The protective effect of OLDA is void in TRPV1−/− hearts, supporting the notion that TRPV1 mediates OLDA-induced protection against cardiac I/R injury.

scholarly journals Protective Effects of TRPV1 Activation Against Cardiac Ischemia/ Reperfusion Injury is Blunted by Diet-Induced Obesity

2020 ◽  
Vol 20 (2) ◽  
pp. 122-130
Author(s):  
Beihua Zhong ◽  
Shuangtao Ma ◽  
Donna H. Wang
Keyword(s):  
Infarct Size ◽  
Transient Receptor Potential ◽  
Diastolic Pressure ◽  
Gene Knockout ◽  
Ischemia Reperfusion ◽  
Control Diet ◽  
Left Ventricular ◽  
Transient Receptor Potential Vanilloid ◽  
Trpv1 Channels ◽  
Postischemic Recovery

Background: Activation of Transient Receptor Potential Vanilloid Subtype 1 (TRPV1) channels protects the heart from Ischemia/Reperfusion (I/R) injury through releasing Calcitonin Gene-Related Peptide (CGRP) and Substance P (SP). The current study aimed to study the cardioprotective effects of TRPV1 in obesity. Methods: TRPV1 gene knockout (TRPV1-/-) and Wild-Type (WT) mice were Fed a High-Fat Diet (HFD) or a control diet or for 20 weeks, and then the hearts were collected for I/R injury ex vivo. The hearts were mounted on a Langendorff apparatus and subjected to ischemia (30 min) and reperfusion (40 min) after incubated with capsaicin (10 nmol/L), CGRP (0.1 μmol/L) and SP (0.1 μmol/L). Then, Coronary Flow (CF), left ventricular peak positive dP/dt (+dP/dt), Left Ventricular Developed Pressure (LVDP) and Left Ventricular End-Diastolic Pressure (LVEDP) were measured. Results: HFD intake remarkably reduced CF, +dP/dt and LVDP and elevated LVEDP in both strains (P<0.05). Treatment with capsaicin decreased infarct size, increased CF, +dP/dt and LVDP, and decreased LVEDP in WT mice on control diet (P<0.05), but did not do so in other three groups. Treatment with CGRP and SP decreased infarct size in both strains fed with control diet (P<0.05). In contrast, not all the parameters of cardiac postischemic recovery in HFD-fed WT and TRPV1-/- mice were improved by CGRP and SP. Conclusions: These results suggest that HFD intake impairs cardiac postischemic recovery. HFDinduced impairment of recovery is alleviated by CGRP in both strains and by SP only in TRPV1-/- mice, indicating that the effects of CGRP and SP are differentially regulated during HFD intake.

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