Myocyte Autophagy in Heart Disease: Friend or Foe?

Rothermel, Beverly A.; Hill, Joseph A.

doi:10.4161/auto.4913

Cited by 66 publications

(46 citation statements)

References 33 publications

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“…The here observed increase of LC3-II in Doxo-treated cardiomyocytes indicates the formation of an increased number of autophagosomes already at lower doses of Doxo. At present, there is no clear consensus in the literature to which extent this pathway of organelle degradation contributes to cardiac survival or to even further deterioration (Rothermel and Hill 2007). The absence of cell death under these conditions supports the notion that this type of contractile dysfunction is potentially reversible, although we cannot exclude, that the accumulation of degraded proteins and damage to genetic material might lead to cell death at a later time point.…”

Section: Discussionmentioning

confidence: 70%

The role of cell death and myofibrillar damage in contractile dysfunction of long-term cultured adult cardiomyocytes exposed to doxorubicin

et al. 2009

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In failing hearts cardiomyocytes undergo alterations in cytoskeleton structure, contractility and viability. It is not known presently, how stress-induced changes of myofibrils correlate with markers for cell death and contractile function in cardiomyocytes. Therefore, we have studied the progression of contractile dysfunction, myofibrillar damage and cell death in cultured adult cardiomyocytes exposed to the cancer therapy doxorubicin. We demonstrate, that long-term cultured adult cardiomyocytes, a wellestablished model for the study of myofibrillar structure and effects of growth factors, can also be used to assess contractility and calcium handling. Adult rat ventricular myocytes (ARVM) were isolated and cultured for a total of 14 days in serum containing medium. The organization of calcium-handling proteins and myofibrillar structure in freshly isolated and in long-term cultured adult cardiomyocytes was studied by immunofluorescence and electron microscopy. Excitation contraction-coupling was analyzed by fura 2 and video edge detection in electrically paced cardiomyocytes forming a monolayer, and cell death and viability was measured by TUNEL assay, LDH release, MTT assay, and Western blot for LC3. Adult cardiomyocytes treated with Doxo showed apoptosis and necrosis only at supraclinical concentrations. Treated cells displayed merely alterations in cytoskeleton organization and integrity concomitant with contractile dysfunction and up-regulation of autophagosome formation, but no change in total sarcomeric protein content. We propose, that myofibrillar damage contributes to contractile dysfunction prior to cell death in adult cardiomyocytes exposed to clinically relevant concentrations of anthracyclines.

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Section: Discussionmentioning

confidence: 70%

The role of cell death and myofibrillar damage in contractile dysfunction of long-term cultured adult cardiomyocytes exposed to doxorubicin

et al. 2009

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“…Though autophagy is essential for recycling macromolecular proteins and removal of damaged organelles during cellular crisis, inappropriate or excessive autophagy beyond a certain threshold is maladaptive and incompatible with life. 6,7 Hence, the differential outcomes of autophagy vis a vis life versus death may reflect the temporal activation of autophagy in a cell and context-specific manner. 8 For example, in the context of ischemia-reperfusion injury, activation of autophagy during the early ischemic phase before reperfusion is considered protective, whereas late or delayed activation of autophagy during reperfusion is detrimental.…”

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confidence: 99%

p53 Mediates Autophagy and Cell Death by a Mechanism Contingent On Bnip3

et al. 2013

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Abstract-Myocardial ischemia and angiotensin II activate the tumor suppressor p53 protein, which promotes cell death.Previously, we showed that the Bcl-2 death gene Bnip3 is highly induced during ischemia, where it triggers mitochondrial perturbations resulting in autophagy and cell death. However, whether p53 regulates Bnip3 and autophagy is unknown. Herein, we provide new compelling evidence for a novel signaling axis that commonly links p53 and Bnip3 for autophagy and cell death. p53 overexpression increased endogenous Bnip3 mRNA and protein levels resulting in mitochondrial defects leading to loss of mitochondrial ∆Ψ m . This was accompanied by an increase in autophagic flux and cell death. Notably, genetic loss of function studies, such as Atg7 knock-down or pharmacological inhibition of autophagy with 3-methyl adenine, suppressed cell death induced by p53-indicating that p53 induces maladaptive autophagy. Our previous work demonstrated that Bnip3 induces mitochondrial defects and autophagic cell death. Conversely, loss of function of Bnip3 in cardiac myocytes or Bnip3 −/− mouse embryonic fibroblasts prevented mitochondrial targeting of p53, autophagy, and cell death. To our knowledge, these data provide the first evidence for the dual regulation of autophagy and cell death of cardiac myocytes by p53 that is mutually dependent on and obligatorily linked to Bnip3 gene activation. Hence, our findings may explain more fundamentally, how, autophagy and cell death are dually regulated during cardiac stress conditions where p53 is activated.

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“…ER stress activates the unfolded protein response (UPR), a set of signaling pathways that halt cellular processes such as protein translation and that upregulate expression of chaperone proteins to restore normal ER function. However, when chronically activated, some UPR pathways can lead to autophagy and cell death (16,40,58,59). Glp1r activation decreases ER stress in pancreatic ␤-cells in response to both hyperglycemic and hyperlipidemic challenge (6,60) and prevents ER stress-induced cell death in pancreatic microendothelial cells (13).…”

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confidence: 99%