Cell Death in the Pathogenesis of Heart Disease: Mechanisms and Significance

Whelan, Russell S.; Kaplinskiy, Vladimir; Kitsis, Richard N.

doi:10.1146/annurev.physiol.010908.163111

Cited by 660 publications

(547 citation statements)

References 163 publications

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“…Autophagy means self-eating in Greek and can function as an intracellular recycling system by which intracellular contents and damaged organelles undergo degradation through their sequestration within autophagosomes and lysosomal degradation to supply energy substrates. [145][146][147][148][149][150][151][152][153] mTORC1 is a critical negative regulator of autophagy. 40,59,154 mTORC1 phosphorylates and inhibits the autophagy-activating kinase ULK1.…”

Section: Hk-ii-mediated Regulation Of Mtorc1 and Autophagymentioning

confidence: 99%

Hexokinase II integrates energy metabolism and cellular protection: Akting on mitochondria and TORCing to autophagy

2014

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Accumulating evidence reveals that metabolic and cell survival pathways are closely related, sharing common signaling molecules. Hexokinase catalyzes the phosphorylation of glucose, the rate-limiting first step of glycolysis. Hexokinase II (HK-II) is a predominant isoform in insulin-sensitive tissues such as heart, skeletal muscle, and adipose tissues. It is also upregulated in many types of tumors associated with enhanced aerobic glycolysis in tumor cells, the Warburg effect. In addition to the fundamental role in glycolysis, HK-II is increasingly recognized as a component of a survival signaling nexus. This review summarizes recent advances in understanding the protective role of HK-II, controlling cellular growth, preventing mitochondrial death pathway and enhancing autophagy, with a particular focus on the interaction between HK-II and Akt/mTOR pathway to integrate metabolic status with the control of cell survival.

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Section: Hk-ii-mediated Regulation Of Mtorc1 and Autophagymentioning

confidence: 99%

Hexokinase II integrates energy metabolism and cellular protection: Akting on mitochondria and TORCing to autophagy

2014

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“…A similar difference in mir-29a(4) expression between fetal and adult skeletal muscle indicates a more ubiquitous antiproliferative role of mir-29a(4). Of note, HF is associated with loss of cardiomyocytes (43) and the mammalian heart has a very limited regenerative capacity (44). The reactivation of self-repair mechanisms by targeting miRNAs represents a possible approach to enhance regeneration (45).…”

Section: Discussionmentioning

confidence: 99%

Comparative RNA-sequencing analysis of myocardial and circulating small RNAs in human heart failure and their utility as biomarkers

Akat

Moore-McGriff

Morozov

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

216

210

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Heart failure (HF) is associated with high morbidity and mortality and its incidence is increasing worldwide. MicroRNAs (miRNAs) are potential markers and targets for diagnostic and therapeutic applications, respectively. We determined myocardial and circulating miRNA abundance and its changes in patients with stable and end-stage HF before and at different time points after mechanical unloading by a left ventricular assist device (LVAD) by small RNA sequencing. miRNA changes in failing heart tissues partially resembled that of fetal myocardium. Consistent with prototypical miRNAtarget-mRNA interactions, target mRNA levels were negatively correlated with changes in abundance for highly expressed miRNAs in HF and fetal hearts. The circulating small RNA profile was dominated by miRNAs, and fragments of tRNAs and small cytoplasmic RNAs. Heart-and muscle-specific circulating miRNAs (myomirs) increased up to 140-fold in advanced HF, which coincided with a similar increase in cardiac troponin I (cTnI) protein, the established marker for heart injury. These extracellular changes nearly completely reversed 3 mo following initiation of LVAD support. In stable HF, circulating miRNAs showed less than fivefold differences compared with normal, and myomir and cTnI levels were only captured near the detection limit. These findings provide the underpinning for miRNA-based therapies and emphasize the usefulness of circulating miRNAs as biomarkers for heart injury performing similar to established diagnostic protein biomarkers.exRNA | body fluids | miRNA-mRNA regulation | development | cardiovascular disease

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“…Several studies reported a role for autophagy in programmed cell death type II (nonapoptotic death) in heart disease [15,16] and indicated that excessive autophagy could lead to cell death. Valentim et al [17] showed that inhibition of autophagy, by both genetic and pharmacological inhibition of Beclin 1, reduced cell death in cardiomyocytes subjected to simulated ischemia-reperfusion.…”

Section: Discussionmentioning

confidence: 99%

Salvianolic acid B inhibits autophagy and protects starving cardiac myocytes

Han

Liu

2010

Acta Pharmacol Sin

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Aim: To investigate the protective or lethal role of autophagy and the effects of Salvianolic acid B (Sal B) on autophagy in starving myocytes. Methods: Cardiac myocytes were incubated under starvation conditions (GD) for 0, 1, 2, 3, and 6 h. Autophagic flux in starving cells was measured via chloroquine (3 µmol/L). After myocytes were treated with Sal B (50 µmol/L) in the presence or absence of chloroquine (3 µmol/L) under GD 3 h, the amount of LC3-II, the abundance of LC3-positive fluorescent dots in cells, cell viability and cellular ATP levels were determined using immunoblotting, immunofluorescence microscopy, MTT assay and luminometer, respectively. Moreover, electron microscopy (EM) and immunofluorescent duel labeling of LC3 and Caspase-8 were used to examine the characteristics of autophagy and apoptosis. Results: Immunoblot analysis showed that the amount of LC3-II in starving cells increased in a time-dependent manner accompanied by increased LC3-positive fluorescence and decreased cell viability and ATP content. Sal B (50 µmol/L) inhibited the increase in LC3-II, reduced the abundance of LC3 immunofluorescence and intensity of Caspase-8 fluorescence, and enhanced cellular viability and ATP levels in myocytes under GD 3 h, regardless of whether chloroquine was present. Conclusion: Autophagy induced by starvation for 3 h led to cell injury. Sal B protected starving cells by blocking the early stage of autophagic flux and inhibiting apoptosis that occurred during autophagy.

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Cell Death in the Pathogenesis of Heart Disease: Mechanisms and Significance

Cited by 660 publications

References 163 publications

Hexokinase II integrates energy metabolism and cellular protection: Akting on mitochondria and TORCing to autophagy

Hexokinase II integrates energy metabolism and cellular protection: Akting on mitochondria and TORCing to autophagy

Comparative RNA-sequencing analysis of myocardial and circulating small RNAs in human heart failure and their utility as biomarkers

Salvianolic acid B inhibits autophagy and protects starving cardiac myocytes

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