Andriy Nemchenko

Cardiomyocyte death: mechanisms and translational implications

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide. Although treatments have improved, development of novel therapies for patients with CVD remains a major research goal. Apoptosis, necrosis, and autophagy occur in cardiac myocytes, and both gradual and acute cell death are hallmarks of cardiac pathology, including heart failure, myocardial infarction, and ischemia/reperfusion. Pharmacological and genetic inhibition of autophagy, apoptosis, or necrosis diminishes infarct size and improves cardiac function in these disorders. Here, we review recent progress in the fields of autophagy, apoptosis, and necrosis. In addition, we highlight the involvement of these mechanisms in cardiac pathology and discuss potential translational implications.

Intracellular Protein Aggregation Is a Proximal Trigger of Cardiomyocyte Autophagy

Background— Recent reports demonstrate that multiple forms of cardiovascular stress, including pressure overload, chronic ischemia, and infarction-reperfusion injury, provoke an increase in autophagic activity in cardiomyocytes. However, nothing is known regarding molecular events that stimulate autophagic activity in stressed myocardium. Because autophagy is a highly conserved process through which damaged proteins and organelles can be degraded, we hypothesized that stress-induced protein aggregation is a proximal trigger of cardiomyocyte autophagy. Methods and Results— Here, we report that pressure overload promotes accumulation of ubiquitinated protein aggregates in the left ventricle, development of aggresome-like structures, and a corresponding induction of autophagy. To test for causal links, we induced protein accumulation in cultured cardiomyocytes by inhibiting proteasome activity, finding that aggregation of polyubiquitinated proteins was sufficient to induce cardiomyocyte autophagy. Furthermore, attenuation of autophagic activity dramatically enhanced both aggresome size and abundance, consistent with a role for autophagic activity in protein aggregate clearance. Conclusions— We conclude that protein aggregation is a proximal trigger of cardiomyocyte autophagy and that autophagic activity functions to attenuate aggregate/aggresome formation in heart. Findings reported here are the first to demonstrate that protein aggregation occurs in response to hemodynamic stress, situating pressure-overload heart disease in the category of proteinopathies.

Energy-preserving effects of IGF-1 antagonize starvation-induced cardiac autophagy

AIMS Insulin-like growth factor 1 (IGF-1) is known to exert cardioprotective actions. However, it remains unknown if autophagy, a major adaptive response to nutritional stress, contributes to IGF-1-mediated cardioprotection. METHODS AND RESULTS We subjected cultured neonatal rat cardiomyocytes, as well as live mice, to nutritional stress and assessed cell death and autophagic rates. Nutritional stress induced by serum/glucose deprivation strongly induced autophagy and cell death, and both responses were inhibited by IGF-1. The Akt/mammalian target of rapamycin (mTOR) pathway mediated the effects of IGF-1 upon autophagy. Importantly, starvation also decreased intracellular ATP levels and oxygen consumption leading to AMP-activated protein kinase (AMPK) activation; IGF-1 increased mitochondrial Ca(2+) uptake and mitochondrial respiration in nutrient-starved cells. IGF-1 also rescued ATP levels, reduced AMPK phosphorylation and increased p70(S6K) phosphorylation, which indicates that in addition to Akt/mTOR, IGF-1 inhibits autophagy by the AMPK/mTOR axis. In mice harbouring a liver-specific igf1 deletion, which dramatically reduces IGF-1 plasma levels, AMPK activity and autophagy were increased, and significant heart weight loss was observed in comparison with wild-type starved animals, revealing the importance of IGF-1 in maintaining cardiac adaptability to nutritional insults in vivo. CONCLUSION Our data support the cardioprotective actions of IGF-1, which, by rescuing the mitochondrial metabolism and the energetic state of cells, reduces cell death and controls the potentially harmful autophagic response to nutritional challenges. IGF-1, therefore, may prove beneficial to mitigate damage induced by excessive nutrient-related stress, including ischaemic disease in multiple tissues.

Diabetic cardiomyopathy and metabolic remodeling of the heart

The incidence and prevalence of diabetes mellitus are both increasing rapidly in societies around the globe. The majority of patients with diabetes succumb ultimately to heart disease, much of which stems from atherosclerotic disease and hypertension. However, the diabetic milieu is itself intrinsically noxious to the heart, and cardiomyopathy can develop independent of elevated blood pressure or coronary artery disease. This process, termed diabetic cardiomyopathy, is characterized by significant changes in the physiology, structure, and mechanical function of the heart. Presently, therapy for patients with diabetes focuses largely on glucose control, and attention to the heart commences with the onset of symptoms. When the latter develops, standard therapy for heart failure is applied. However, recent studies highlight that specific elements of the pathogenesis of diabetic heart disease are unique, raising the prospect of diabetes-specific therapeutic intervention. Here, we review recently unveiled insights into the pathogenesis of diabetic cardiomyopathy and associated metabolic remodeling with an eye toward identifying novel targets with therapeutic potential.

NEMO nuances NF-κB

See related article, pages 133–144 Stress-induced adverse remodeling of the myocardium is a major mechanism leading to heart failure, a leading and rapidly escalating source of morbidity and mortality worldwide.1,2 As a result, much work is underway to dissect molecular mechanisms governing cardiac remodeling in hopes of identifying novel therapeutic targets. In recent years, much of this work has focused on the hypertrophic growth response of the cardiac myocyte. Initially adaptive, cardiac hypertrophy compensates for declines in cardiac performance and increases in wall stress; sustained hypertrophy, however, is a major risk factor for emergence of systolic dysfunction and clinical heart failure.3 On the bright side, numerous preclinical studies have demonstrated that abrogation of the hypertrophic response is well tolerated, and even beneficial.4 One potential target of therapy in the pathologically remodeled, hypertrophied heart is the transcription factor nuclear factor (NF)-κB. First discovered more than 20 years ago, NF-κB has been linked to numerous neurohormonal, pathophysiological, and stress stimuli responses, and it has been characterized most extensively in the immune system. In the heart, activation of NF-κB-dependent transcription has been detected in numerous disease contexts, including hypertrophy, ischemia/reperfusion injury, myocardial infarction, allograft rejection, myocarditis, apoptosis, and more.5,6 Within coronary vessels, NF-κB has been implicated in atherosclerosis and restenosis.5,6 However, parsing the specific role(s) of NF-κB in these diverse disease processes has been hampered by the embryonic lethality of inactivation of several NF-κB components.7–9 In heart, the NF-κB family of transcription factors comprises 4 members: p50, p52, p65, and RelB. All are capable of multimerization, forming either homo- or heterodimers, but the ubiquitously expressed p50 and p65 (herein termed NF-κB) are responsible for the majority of NF-κB binding activity in the myocardium. Activation of cytoplasmic NF-κB requires phosphorylation and subsequent proteasome-dependent degradation of its repressor, …

Highlights from this issue: Andriy Nemchenko

Multiple skeletal muscle myopathies were linked to mutations in extracellular matric protein collagen VI. Later reports noted impaired activation of autophagy in collagen VI-deficient mice. Paolo Bonaldo’s group, in this study (see editorial and basic brief report by Grumati et al. in this issue), hypothesized that reactivation of autophagy by exercise might improve mitochondrial biogenesis and ultimately muscle homeostasis. According to the authors, long-term and short bursts of exercise induce autophagy in normal muscle. Unlike WT, collagen VI-deficient mice, Col6a, fail to activate autophagy in response to exercise and display severe muscle dystrophy.

There is more to autophagy than induction: regulating the roller coaster.

Considerable attention has been paid to the topic of autophagy induction. In part, this is because of the potential for modulating this process for therapeutic purposes. Of course we know that induced autophagy can also be problematic—for example, when trying to eliminate an established tumor that might be relying on autophagy for its own cytoprotective uses. Accordingly, inhibitory mechanisms have been considered; however, the corresponding studies have tended to focus on the pathways that block autophagy under noninducing conditions, such as when nutrients are available. In contrast, relatively little is known about the mechanisms for inhibiting autophagy under inducing conditions. Yet, this type of regulation must be occurring on a routine basis. We know that dysregulation of autophagy, e.g., due to improper activation of Beclin 1 leading to excessive autophagy activity, can cause cell death.1 Accordingly, we assume that during starvation or other inducing conditions there must be a mechanism to modulate autophagy. That is, once you turn it on, you do not want to let it continue unchecked. But how is autophagy downregulated when the inducing conditions still exist?