Intensity, Duration, and Context Dependency of the Responses to Nutrient Surplus and Deprivation Signaling in the Heart: Insights Into the Complexities of Cardioprotection

Nutrient surplus sensing through PI3K (phosphoinositide-3-kinase) and mTOR (mechanistic target of rapamycin) stimulates anabolism to expand cellular mass, whereas nutrient and energy deprivation sensing through SIRT1 (sirtuin-1) and AMPK (adenosine monophosphate-activated protein kinase) promotes catabolism to support cytoprotective quiescence. By signaling through downstream effectors (PGC-1α peroxisome proliferator-activated receptor gamma coactivator 1-alpha, PPARα/PPARγ, FoxO1 forkhead box protein family O1, NRF2 nuclear factor erythroid-derived factor 2, HIF-1α hypoxia-inducible factor-1α, and HO-1 heme oxygenase-1), environmental nutrients, growth factors, and cellular stress influence mitochondrial biogenesis, autophagic flux, cardiac hypertrophy, and cardiomyocyte senescence and apoptosis. Despite these canonical descriptions, the actual response to each effector is determined by the intensity and duration of signaling. Typically, transient and measured signaling produces adaptive effects, whereas continuous heightened activity yields maladaptive responses. The effects of signaling are also influenced by context; ie, the nature and intermittency of the external stress and the characteristics of the underlying substrate (eg, cardiomyopathy, obesity, or aging). PI3K signaling promotes physiological hypertrophy and is cardioprotective during abrupt cardiac stress, but its sustained activation accelerates pathological hypertrophy related to obesity and aging. Signaling through SIRT1/AMPK (and upregulation of autophagic flux) exerts favorable effects during exercise training and in chronic cardiomyopathy, obesity, and aging, but it undermines the cardiac response to abrupt stress. Intermittent FoxO1 upregulation may promote physiological hypertrophy while antagonizing pathological hypertrophy, but prolonged activation leads to cardiomyocyte apoptosis. NRF2 exerts antioxidant effects when background autophagic flux is vigorous but aggravates cellular stress when autophagy is suppressed (as in pathological hypertrophy). Sustained activation of PPARγ, NRF2, and HIF-1α in nutrient surplus states can lead to maladaptive ventricular remodeling, thus explaining the results of clinical trials with thiazolidinediones, bardoxolone, and prolyl hydroxylase inhibitors. The influence of duration, intensity, and context may be mediated (in part) by the activation or suppression of counterregulatory mechanisms, by the selective recruitment of corepressors, and by posttranslational protein modifications. These observations, considered collectively, suggest that no protein or cellular process viewed in isolation can be regarded as cardioprotective or maladaptive. Cell signals operate usefully if they are delivered as part of an orchestrated program of compartmentalized nuanced bursts, acting as elements of multifaceted oscillating systems whose periodicity is determined by the need to achieve homeostasis.