Blue LEDs get the Nobel Prize while Red LEDs are poised to save lives

Ischemic heart disease is a major public health epidemic and a leading cause of morbidity and mortality worldwide (Hausenloy et al., 2012; Ferdinandy et al., 2014). Ischemic injury predisposes to myocardial infarction, heart failure, arrhythmias, and sudden cardiac death. Prompt restoration of oxygenated blood flow to the ischemic myocardium (i.e., reperfusion) is required for preventing irreversible cell damage and death. Unfortunately, restoration of blood flow, in itself, results in additional cardiac damage, known as reperfusion injury. Such oxidative damage, which is mediated by bursts of reactive oxygen species (ROS), is more severe when reperfusion therapy is delayed. Indeed, necrotic cell death as a consequence of ROS overproduction can paradoxically exacerbate the extent of myocardial infarction. Concomitantly, reperfusion-mediated cytosolic calcium overload and redox imbalance promote mechanoelectrical dysfunction and arrhythmias. In recent years, mitochondria have emerged as central mediators of cell death and survival pathways (O’Rourke et al., 2005). On the one hand, opening of energy-dissipating mitochondrial channels that destabilize the mitochondrial membrane potential, such as the permeability transition pore (PTP) and the inner membrane anion channel (IMAC), result in myocardial infarction (Hausenloy et al., 2012) and arrhythmias (Akar et al., 2005), respectively. On the other hand, the seminal discovery of intrinsic cardioprotective pathways that stem from a mitochondrial origin has provided hope for combatting ischemia-reperfusion injury along with its pathological manifestations (impaired contractile recovery, arrhythmias, and myocardial infarction) (Murry et al., 1986). In particular, the proven efficacy of ischemic preand postconditioning protocols in limiting the damage imposed by the index ischemic event has provided researchers with an effective tool for uncovering endogenous cardioprotective signaling pathways, with the promise of identifying molecular targets that can be manipulated pharmacologically (Ferdinandy et al., 2014). Prominent amongst such targets are ATP-sensitive potassium channels in the mitochondrial membrane (mKATP) which are tightly regulated by PKC signaling. Although the molecular identity of these channels has eluded discovery for many years, recent work by the O’Rourke laboratory convincingly points to ROMK as a viable candidate (Foster et al., 2012). Nonetheless mKATP activation by diazoxide is cardioprotective against ischemia-reperfusion injury. Another key target is the PTP whose opening represents a terminal event that causes necrotic cell death. Indeed, Hausenloy and others have shown that PTP inhibition using cyclosporine-A (CsA) effectively limits the extent of myocardial infarction (Hausenloy et al., 2012). Whether CsA protects or exacerbates post-ischemic electrical dysfunction, however, remains a matter of debate. This issue may be complicated by PKC-dependent cross-talk between the PTP and mKATP channels which we recently examined (Xie et al., 2014). Moreover, post-ischemic arrhythmias can be suppressed by stabilizing the mitochondrial membrane potential using antagonists of the peripheral benzodiazepine receptor which modulates IMAC (Akar et al., 2005). The efficacy of this strategy in limiting infarct size, however, has not been systematically tested. Finally, volatile anesthetics have also been shown to reduce reperfusion injury likely by targeting mitochondrial pathways (Agarwal et al., 2014). Because pharmacological therapies for reperfusion injury have proven difficult, novel approaches for this epidemic are much needed. In this issue of the journal, Keszler et al. (2014) focused on a highly innovative non-pharmacological strategy. Specifically, they were able to harness the power of near-infrared (NIR) lightemitting diodes (LEDs) to liberate nitric oxide (NO) in a manner that exerted a potent cardioprotective effect. The findings of Keszler et al. (2014) are exciting on several grounds. Not only did these authors expand our understanding of the mechanism by which NIR elicits cardioprotection, they convincingly documented its utility in the setting of diabetes mellitus. This achievement cannot be overstated given the failure of most other cardioprotective strategies,