TRPA1 channel contributes to myocardial ischemia-reperfusion injury

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 Ca2+-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 Ca2+ 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+/Ca2+ exchange inhibitor, further supporting a role of Ca2+ 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 Ca2+ 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.

Interrelation between ROS and Ca2+ in aging and age-related diseases

“…Furthermore, ROS-sensitive TRPA1 channel was found to contribute to Ca 2+ overload and hypercontraction of cardiomyocytes. Genetic ablation of TRPA1 caused a significant decrease in myocardial infarction after I/R in mice, indicating that I/R activation of TRPA1 worsens myocardial infarction [ 149 ]. In addition to channels in the plasma membrane, Ca 2+ transport proteins in ER and mitochondria are also crucial contributors to the development of cardiovascular diseases.…”

Transient Receptor Potential Ankyrin Type-1 Channels as a Potential Target for the Treatment of Cardiovascular Diseases

“…TRPA1 is present in cardiomyocytes and is important in regulating myocardial reperfusion injury ( Lu et al, 2016 ). A study showed that TRPA1 gene-knockout myocardial ischemia–reperfusion mice alleviated myocardial injury, indicating that TRPA1 channel activation mediates myocardial ischemia–reperfusion injury ( Conklin et al, 2019 ). This may be related to the accumulation of free radicals and unsaturated aldehydes generated after myocardial ischemia and reperfusion to activate TRPA1 channel.…”

The cardiac TRPA1 channel drives calcium-mediated mechano-arrhythmogenesis

“…This is especially true for diseases in which additional factors that activate TRPA1 channels are present (e.g., oxidative stress 36 ), as the response of TRPA1 channels to mechanical stimulation is enhanced by an increase in its baseline activity 9 . For instance, acute myocardial ischemia resulting from blockage of a / 35 coronary artery is associated with TRPA1-mediated myocardial damage 13 and lethal ventricular arrhythmias that are thought to involve contributions of altered tissue mechanics, intracellular Ca 2+ handling, and oxidative stress 37 , so targeting TRPA1 channels in that setting could help prevent multiple detrimental outcomes (and perhaps even promote post-ischemic myocardial repair 14 ).…”