The second member of transient receptor potential-melastatin channel family protects hearts from ischemia-reperfusion injury

Abstract

The second member of the transient receptor potential-melastatin channel family (TRPM2) is expressed in the heart and vasculature. TRPM2 channels were expressed in the sarcolemma and transverse tubules of adult left ventricular (LV) myocytes. Cardiac TRPM2 channels were functional since activation with H2O2 resulted in Ca(2+) influx that was dependent on extracellular Ca(2+), was significantly higher in wild-type (WT) myocytes compared with TRPM2 knockout (KO) myocytes, and inhibited by clotrimazole in WT myocytes. At rest, there were no differences in LV mass, heart rate, fractional shortening, and +dP/dt between WT and KO hearts. At 2-3 days after ischemia-reperfusion (I/R), despite similar areas at risk and infarct sizes, KO hearts had lower fractional shortening and +dP/dt compared with WT hearts. Compared with WT I/R myocytes, expression of the Na(+)/Ca(2+) exchanger (NCX1) and NCX1 current were increased, expression of the α1-subunit of Na(+)-K(+)-ATPase and Na(+) pump current were decreased, and action potential duration was prolonged in KO I/R myocytes. Post-I/R, intracellular Ca(2+) concentration transients and contraction amplitudes were equally depressed in WT and KO myocytes. After 2 h of hypoxia followed by 30 min of reoxygenation, levels of ROS were significantly higher in KO compared with WT LV myocytes. Compared with WT I/R hearts, oxygen radical scavenging enzymes (SODs) and their upstream regulators (forkhead box transcription factors and hypoxia-inducible factor) were lower, whereas NADPH oxidase was higher, in KO I/R hearts. We conclude that TRPM2 channels protected hearts from I/R injury by decreasing generation and enhancing scavenging of ROS, thereby reducing I/R-induced oxidative stress.

TRPM2 mediates ischemic kidney injury and oxidant stress through RAC1

“…Number 11 November 2014 present study, Miller et al (43) found that an absence of TRPM2 exacerbated myocardial ischemic injury and increased oxidative stress, whereas we found a reduction in both ischemic injury and oxidative stress in the kidney. The reasons underlying the differential responses to coronary versus kidney ischemia in the same Trpm2-KO mouse are not clear but may relate to different functions for ion channels and intracellular calcium regulation in epithelia and excitable tissues.…”

“…Conversely, TRPM2 is inhibited by low temperature and acidosis, both of which reduce ischemic AKI (46,47). We explored the role of TRPM2 in AKI in vivo using a newly developed Trpm2-KO mouse (43). Our studies yielded several important findings.…”

“…A number of previous studies have reported that TRPM2 is capable of sensing and responding to oxidative stress and that it plays a critical role in cell proliferation and oxidant-induced cell death in vitro (16,23). However, the role of TRPM2 in disease processes in vivo is poorly understood due to the lack of specific inhibitors and the only recent development of KO models (43)(44)(45). Nonetheless, TRPM2 has several features that make it an attractive candidate to mediate ischemic AKI.…”

Ca2+entry via Trpm2 is essential for cardiac myocyte bioenergetics maintenance

“…To form a functional channel, Trp proteins assemble into either homo-or heterotetramers, with the putative pore formed by loops between the fifth and sixth TM domains (21,23). The Trp-melastatin (Trpm) subfamily consists of eight mammalian members (Trpm1-Trpm8) (30), of which Trpm2 (27), -m4, -m5, and -m6 (49) are expressed in the heart. Although Trpm4 is associated with conduction abnormalities and cardiac arrhythmias (1,36), there is little information on the physiological and pathophysiological function of Trpm2 in the heart.…”

“…Trpm2 is expressed in the sarcolemma and transverse (t) tubules in adult mouse ventricular myocytes (27). In adult cardiac myocytes, Trpm2 is activated by H 2 O 2 and intracellular adenosine diphosphate-ribose (ADPR), inhibited by clotrimazole and flufenamic acid, does not inactivate, and has a conductance for Ca 2ϩ that is ϳ50% of Na ϩ (26,27).…”