Beneficial Effects Induced by TRPM8 Channels Activation to Treat Myocardial Infarction

Undoubtedly, cardiovascular diseases are and will continue to be one of the major health problems of modern society.1 It is estimated that in 2015, coronary heart disease was responsible for 7.4 million deaths, with myocardial infarction (MI) as the most common form of coronary heart disease.1 Obstruction of coronary artery causes MI, which results in reduced regional blood flow within the cardiac muscle.2 Following acute MI, several alterations occur, including change of the ventricular shape and structure, commonly known as ventricular remodeling.3 In fact, despite the adoption of the best available strategies for restoration of the infarct-related artery patency, almost 30% of patients with ST segment elevated MI still develop left ventricular dysfunction and remodeling.4 Interestingly, transient receptor potential (TRP) channels are involved in various pathological mechanisms in the heart, including arrhythmias, ischemia–reperfusion injuries, Ca2+-handling defects, fibrosis, inherited cardiopathies, as well as demonstrating involvement in different stages of the cardiac remodeling process postinjury.5 Importantly and extremely relevant, new biological targets are being investigated, that mitigate cardiac remodeling following MI. The TRP receptors, a family of Ca2+-entry channels, are multimodally activated and display relevant characteristics of both acute hemodynamic control and long-term remodeling of the cardiovascular system.6 Among the TRP channels subtypes, TRP melastatin 8 (TRPM8), recognized as thermo-TRPs, is a nonselective calcium-permeable channel, mainly localized in sensory neurons, that plays a critical role in the transduction of moderate cold stimuli.7 TRPM8 behaves as a polymodal receptor and may be activated by different stimuli, such as: membrane depolarization, cold, chemical compounds (menthol and icilin), and several inflammatory agents.8 The functional role of TRP channels has also been shown to be critically involved in natural products actions.9 Among the various plant constituents, monoterpenes are the most represented molecules found in plant-derived essential oils.10 In addition, among the many monoterpenes that directly act on TRP channels, menthol is well known as a selective TRPM8 channel agonist.7 Some studies have shown the beneficial effects of menthol and/or TRPM8 activation in different cardiovascular diseases settings. The activation of the TRPM8 channel with chronic dietary application of menthol reduced blood pressure in spontaneous hypertensive rats, attenuated vasoconstriction and activation of Rho-Kinase (ROCK) pathways in the vasculatures.11,12 These results establish a strong connection in cardiac diseases, due to the fact that in MI patients, a Rho/ROCK activity is increased.13 The literature reports that insufficient oxygen supply during prolonged ischemia causes cardiac cell death and reactive oxygen species (ROS) generation, conditions that are involved in ischemic occlusion and lead to cardiac injury.14 According Bidaux and colleagues, in HaCaT human keratinocyte cell line, the TRPM8 channels appear to regulate mitochondrial function and ROS production by coupling the endoplasmic reticulum membrane (where TRPM8 is located) with mitochondria, thereby affecting mitochondrial calcium concentration.15 Menthol-induced mitochondrial Ca2+ transients in smooth muscle cells from the aorta promote increased pyruvate dehydrogenase activity, improved mitochondrial respiratory activity, decreased ROS production and reduced Ca2+ flow in wild type mice, but not in TRPM8 channel knockout mice. Additionally, long-term dietary menthol treatment, TRPM8 channels coupled sarcoplasmic reticulum Ca2+ release to mitochondrial Ca2+ uptake, as well as inhibited both ROS production and the expression of RhoA-GTP in TRPM8-dependent manner.11 The TRPM8 channels appear to act in a protective manner within the cardiovascular system, although the mechanisms involved in these responses are not fully understood. As mentioned above, activation by menthol attenuates the inflammation and the production of ROS, as well as ROCK expression and function, which can it be beneficial in the prevention and treatment of cardiovascular disease, however, the effects of TRPM8 channels on inflammation and cardiac remodeling, following MI, it is not completely elucidated. Studies evaluating the role of TRP channels, including TRPM8 channels, are increasingly challenging due to the lack of selective activators or blockers, thus limiting studies to knockout models or RNA interference assays to assess the cellular effects underlying the activation of these channels. However, although Cheng and colleagues did not use TRPM8 knockout models, they demonstrated that TRPM8 protein and mRNA were expressed in rat myocardium. In addition, using an animal model of myocardial ischemia/reperfusion injury (MIRI), hypothermic cardiac reperfusion decreased the infarct size, lactate dehydrogenase, malondialdehyde, apoptosis, and expression of RhoA and ROCK2, when compared with normothermic reperfusion. Similar effects were observed following normothermic reperfusion in the presence of icilin, a TRPM8 agonist. Furthermore, these effects were significantly reduced by N-(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carbox-amide, a TRPM8 antagonist, suggesting that hypothermic reperfusion at 25 °C protects the myocardium against myocardial ischemia/reperfusion injury via TRPM8 activation.16 In this issue of the American Journal of Hypertension, Wang and colleagues conducted an experimental study evaluating the effect of menthol-induced TRPM8 activation, on inflammation and cardiac remodeling after MI. This study demonstrated that dietary menthol can protect against inflammation and cardiac remodeling following MI through activation of TRPM8, by promoting a decrease in plasma concentration of cardiac troponin I levels, attenuation of monocyte chemoattractant protein-1, and an reduction in interleukin (IL)-1β, IL-6, tumor necrosis factor-alpha. In addition, menthol increased mice survival rates after MI through TRPM8 activation and the beneficial effect of menthol disappeared in TRPM8 knockout mice, indicating that TRPM8 activation appears to restore cardiac function and hemodynamics in mice post-MI. There remain a few points that are unclear and should be the focus of future investigations. Additionally, the animals were treated with menthol 2 weeks before the surgical procedure to induce MI, thus these animals were subjected to a preventive treatment with TRPM8 activator. What would be the menthol-induced therapeutic effect if it would be administered only after MI, similar to therapy for patients with MI? In addition, all beneficial effects caused by menthol treatment would be by TRPM8 activation in immunological cells, fibroblasts, cardiomyocytes, in sensory nerve or all of these cells and settings together? Therefore, in vitro experiments will be needed to clarify these questions. Although the study showed an attenuation of cytokine and chemokine elevation in MI mice via dietary menthol, another study has shown that TRPM8 channel activation by topic application of menthol promoted an increase of level of proinflammatory cytokines (IL-6 and IL-1β) in the blood of normotensive rats, but not in rats with inherited stress-induced arterial hypertension.17 These results suggest that the regulation of pro-inflammatory cytokines appear to involve the TRPM8 channel participation, but further studies are needed to clarify the exact mechanism of this regulation. Possible menthol mechanisms are illustrated in Figure 1. Schematic diagram of the protective effect induced by transient receptor potential melastatin subtype 8 (TRPM8) activation in heart after myocardial infarction. The menthol diet increased the release of calcitonin gene-related peptide (CGRP), mediated by TRPM8 activation. CGRP modulated immune cell responses causing a reduction of cytokine levels TNF-alpha, IL-6, and IL-1β and reduced postinfarction cardiac fibrosis. It is possible that the activation of TRPM8 by menthol coupled sarcoplasmic reticulum Ca2+ release to mitochondrial Ca2+ uptake, which promotes the activity of pyruvate dehydrogenase (PDH) and mitochondrial oxidative phosphorylation (OXPHOS), inhibiting reactive oxygen species (ROS) generation. In addition, menthol treatment may inhibit the expression of RhoA-GTP. Abbreviations: RhoA, small GTPase protein in the Rho family; ROCK, Rho-kinase; SP, substance P; cTnI, concentration of cardiac troponin I; IL, interleukin; ER, endoplasmic reticulum; CGRP, calcitonin gene-related peptide; MI, myocardial infarction; TNF-alpha, tumor necrosis factor-alpha; TRPM8, transient receptor potential melastatin type 8. In this issue, the authors demonstrated the benefits of preventive menthol treatment of animals with MI and that these effects were not present in TRPM8 knockout animals. However, menthol-induced actions, including calcium signal changing in a TRPM8-independent manner, have already been well documented.18 A monoterpene rotundifolone, was described as a more selective TRPM8 channel activator than menthol,19 however, no studies involving TRPM8 activation and protective cardiac effects after infarction with rotundifolone treatment have been performed. Similar to menthol, other monoterpenes have demonstrated important cardiac remodeling activities. For example, Paeoniflorin, improves cardiac function and decreases adverse postinfarction left ventricular remodeling in a rat model of acute MI. The proposed mechanism of action for Paeoniflorin is through the reduction or inhibition of brain natriuretic peptide, as well as the proinflammatory cytokines tumor necrosis factor-alpha and IL-6, addition to promoting an increase in IL-10.20 Aucubin, another monoterpene, relieves the cardiac remodeling process after MI, in addition to improving heart function and survival rate in mice, through by Neuronal Nitric Oxide Synthases/Nitric Oxide signaling pathway, which, among other effects, attenuates the generation of ROS.21 Although many monoterpenes are able to reduce cardiac remodeling after acute MI, none of these responses were directly associated with TRPM8 channels activation, making the study of Wang and colleagues extremely relevant. TRPM8 channel, beyond the cardioprotective, anti-inflammation and anti-fibrosis roles, appear to be a potential therapeutic target that may improve patients’ clinical condition after acute MI. Thus, further studies are needed to clarify the exact cellular mechanism by which menthol promotes its cardioprotective effects following acute MI, and it would be interesting to evaluate the involvement of ROS and ROCK in the protective mechanisms of menthol. This study was funded by grants from National Council for Scientific and Technological Development (CNPq), process number 233867/2014–7 and 306106/2017–5; Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—Brasil (CAPES)—Finance Code 001; NIDDK Diacomp Pilot & Feasibly Program. The authors declared no conflict of interest.