Stimulation of TRPA1 attenuates ischemia-induced cardiomyocyte cell death through an eNOS-mediated mechanism

Abstract

The functional expression of transient receptor potential cation channel of the ankyrin-1 subtype (TRPA1) has recently been identified in adult mouse cardiac tissue where stimulation of this ion channel leads to increases in adult mouse ventricular cardiomyocyte (CM) contractile function via a Ca 2+ -Calmodulin-dependent kinase (CaMKII) pathway. However, the extent to which TRPA1 induces nitric oxide (NO) production in CMs, and whether this signaling cascade mediates physiological or pathophysiological events in cardiac tissue remains elusive. Freshly isolated CMs from wild-type (WT) or TRPA1 knockout (TRPA1 -/- ) mouse hearts were treated with AITC (100 µM) and prepared for immunoblot, NO detection or ischemia protocols. Our findings demonstrate that TRPA1 stimulation with AITC results in phosphorylation of protein kinase B (Akt) and endothelial NOS (eNOS) concomitantly with NO production in a concentration- and time-dependent manner. Additionally, we found that TRPA1 induced increases in CM [Ca 2+ ] i and contractility occur independently of Akt and eNOS activation mechanisms. Further analysis revealed that the presence and activation of TRPA1 promotes CM survival and viability following ischemic insult via a mechanism partially dependent upon eNOS. Therefore, activation of the TRPA1/Akt/eNOS pathway attenuates ischemia-induced CM cell death.

Energy‐sparing by 2‐methyl‐2‐thiazoline protects heart from ischaemia/reperfusion injury

“…TRPA1 deficiency reportedly ameliorates myocardial I/R injury and mediates enhanced Ca 2+ levels in cardiomyocytes 38,39 . Furthermore, TRPA1 is known to activate the protein kinase B (Akt)/endothelial NOS pathway in cardiomyocytes, resulting in attenuation of ischaemia‐induced cardiomyocyte cell death 40 . These reports suggest that TRPA1 may be directly involved in the effect of subcutaneous 2MT administration on cardiomyocytes, resulting in a cardioprotective effect.…”

“… 38 , 39 Furthermore, TRPA1 is known to activate the protein kinase B (Akt)/endothelial NOS pathway in cardiomyocytes, resulting in attenuation of ischaemia‐induced cardiomyocyte cell death. 40 These reports suggest that TRPA1 may be directly involved in the effect of subcutaneous 2MT administration on cardiomyocytes, resulting in a cardioprotective effect. Further studies are needed to elucidate the detailed systemic and cardiac protective effects of 2MT involving the role of TRPA1 in cellular oxidative stress.…”

TRPA1 and TRPV1, do we hold you in our heart?

“…5 They observed a TRPA1 immunolabelling on freshly isolated mouse cardiomyocytes and modifications of Ca 2+ -transient of these cells after the application of allyl isothiocyanate (AITC), the classical TRPA1 agonist, given that TRPA1 is permeable to cations (five times more permeable for Ca 2+ than for Na + ). 6 The same group has further demonstrated that TRPA1 is involved in cardiomyocytes contraction 7 and protects against ischemia-induced cardiomyocytes death, 8 highlighting physiological and pathological implication in cardiomyocytes. Despite these reports, in the study presented in this issue, Hoebart et al 1 were unable to unmask any TRPA1 signature.…”

No functional TRPA1 in cardiomyocytes

“…Several studies have reported TRPA1 expression, to a lesser extent, in various other cell types, 12‐16 including cardiomyocytes. In murine cardiomyocytes, TRPA1 expression has been reported at mRNA, 17‐19 protein, 20,21 and functional level 22 . In addition, a regulation of its expression in cardiac tissue by insulin‐like growth factor has been described 18 .…”

“…In murine cardiomyocytes, TRPA1 expression has been reported at mRNA, [17][18][19] protein, 20,21 and functional level. 22 In addition, a regulation of its expression in cardiac tissue by insulin-like growth factor has been described. 18 Most important is whether TRPA1 contributes to cardiac physiology and pathophysiology.…”