Journal article
TRPA1 channel contributes to myocardial ischemia-reperfusion injury
American journal of physiology. Heart and circulatory physiology, Vol.316(4), pp.H889-H899
04/01/2019
DOI: 10.1152/ajpheart.00106.2018
PMCID: PMC6483018
PMID: 30735434
Abstract
Myocardial ischemia-reperfusion (I/R) results in the generation of free radicals, accumulation of lipid peroxidation-derived unsaturated aldehydes, variable angina (pain), and infarction. The transient receptor potential ankyrin 1 (TRPA1) mediates pain signaling and is activated by unsaturated aldehydes, including acrolein and 4-hydroxynonenal. The contribution of TRPA1 (a Ca
-permeable channel) to I/R-induced myocardial injury is unknown. We tested the hypothesis that cardiac TRPA1 confers myocyte sensitivity to aldehyde accumulation and promotes I/R injury. Although basal cardiovascular function in TRPA1-null mice was similar to that in wild-type (WT) mice, infarct size was significantly smaller in TRPA1-null mice than in WT mice (34.1 ± 9.3 vs. 14.3 ± 9.9% of the risk region, n = 8 and 7, respectively, P < 0.05), despite a similar I/R-induced area at risk (40.3 ±8.4% and 42.2 ± 11.3% for WT and TRPA1-null mice, respectively) after myocardial I/R (30 min of ischemia followed by 24 h of reperfusion) in situ. Positive TRPA1 immunofluorescence was present in murine and human hearts and was colocalized with connexin43 at intercalated disks in isolated murine cardiomyocytes. Cardiomyocyte TRPA1 was confirmed by quantitative RT-PCR, DNA sequencing, Western blot analysis, and electrophysiology. A role of TRPA1 in cardiomyocyte toxicity was demonstrated in isolated cardiomyocytes exposed to acrolein, an I/R-associated toxin that induces Ca
accumulation and hypercontraction, effects significantly blunted by HC-030031, a TRPA1 antagonist. Protection induced by HC-030031 was quantitatively equivalent to that induced by SN-6, a Na
/Ca
exchange inhibitor, further supporting a role of Ca
overload in acrolein-induced cardiomyocyte toxicity. These data indicate that cardiac TRPA1 activation likely contributes to I/R injury and, thus, that TRPA1 may be a novel therapeutic target for decreasing myocardial I/R injury. NEW & NOTEWORTHY Transient receptor potential ankyrin 1 (TRPA1) activation mediates increased blood flow, edema, and pain reception, yet its role in myocardial ischemia-reperfusion (I/R) injury is unknown. Genetic ablation of TRPA1 significantly decreased myocardial infarction after I/R in mice. Functional TRPA1 in cardiomyocytes was enriched in intercalated disks and contributed to acrolein-induced Ca
overload and hypercontraction. These data indicate that I/R activation of TRPA1 worsens myocardial infarction; TRPA1 may be a potential target to mitigate I/R injury.
Details
- Title: Subtitle
- TRPA1 channel contributes to myocardial ischemia-reperfusion injury
- Creators
- Daniel J Conklin - University of LouisvilleYiru Guo - University of LouisvilleMatthew A Nystoriak - University of LouisvilleGanapathy Jagatheesan - University of LouisvilleDetlef Obal - University of LouisvillePeter J Kilfoil - Cedars-Sinai Smidt Heart InstituteJoseph David Hoetker - University of LouisvilleLuping Guo - University of LouisvilleRoberto Bolli - University of LouisvilleAruni Bhatnagar - University of Louisville
- Resource Type
- Journal article
- Publication Details
- American journal of physiology. Heart and circulatory physiology, Vol.316(4), pp.H889-H899
- DOI
- 10.1152/ajpheart.00106.2018
- PMID
- 30735434
- PMCID
- PMC6483018
- ISSN
- 0363-6135
- eISSN
- 1522-1539
- Grant note
- P30 GM127607 / NIGMS NIH HHS R01 HL142710 / NHLBI NIH HHS P42 ES023716 / NIEHS NIH HHS R01 HL122676 / NHLBI NIH HHS
- Language
- English
- Date published
- 04/01/2019
- Academic Unit
- Anesthesia
- Record Identifier
- 9984696573502771
Metrics
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