Assessment of Autophagy Markers Suggests Increased Activity Following LVAD Therapy

Martin, Thomas G.; Juarros, Miranda A.; Cleveland, Joseph C.; Bristow, Michael R.; Ambardekar, Amrut V.; Buttrick, Peter M.; Leinwand, Leslie A.

doi:10.1016/j.jacbts.2023.05.015

Cited by 5 publications

(2 citation statements)

References 33 publications

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“…The significant correlation found between Beclin 1 and LVEF, the principal determinant of heart failure in MI patients [ 31 ], supports recent data showing the involvement of autophagy (e.g., increased expression of Beclin 1 protein) in left ventricular reverse remodeling following mechanical unloading [ 32 ]. Interestingly, the ROC curve analysis revealed that ATG5 and Beclin 1 could be novel candidate markers for predicting AMI.…”

Section: Discussionsupporting

confidence: 78%

Association of Circulating Autophagy Proteins ATG5 and Beclin 1 with Acute Myocardial Infarction in a Case-Control Study

Grazide,

Ruidavets,

Martinet

et al. 2024

Cardiology

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Introduction: Acute myocardial infarction (AMI) is a main contributor of sudden cardiac death worldwide. The discovery of new biomarkers that can improve AMI risk prediction meets a major clinical need for the identification of high-risk patients and the tailoring of medical treatment. Previously, we reported that autophagy a highly conserved catabolic mechanism for intracellular degradation of cellular components is involved in atherosclerotic plaque phenotype and cardiac pathological remodeling. The crucial role of autophagy in the normal and diseased heart has been well described, and its activation functions as a pro-survival process in response to myocardial ischemia. However, autophagy is dysregulated in ischemia/reperfusion injury, thus promoting necrotic or apoptotic cardiac cell death. Very few studies have focused on the plasma levels of autophagy markers in cardiovascular disease patients, even though they could be companion biomarkers of AMI injury. The aims of the present study were to evaluate (1) whether variations in plasma levels of two key autophagy regulators autophagy-related gene 5 (ATG5) and Beclin 1 (the mammalian yeast ortholog Atg6/Vps30) are associated with AMI and (2) their potential for predicting AMI risk. Methods: The case-control study population included AMI patients (n = 100) and control subjects (n = 99) at high cardiovascular risk but without known coronary disease. Plasma levels of ATG5 and Beclin 1 were measured in the whole population study by enzyme-linked immunosorbent assay. Results: Multivariate analyses adjusted on common cardiovascular factors and medical treatments, and receiver operating characteristic curves demonstrated that ATG5 and Beclin 1 levels were inversely associated with AMI and provided original biomarkers for AMI risk prediction. Conclusion: Plasma levels of autophagy regulators ATG5 and Beclin 1 represent relevant candidate biomarkers associated with AMI.

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Section: Discussionsupporting

confidence: 78%

Association of Circulating Autophagy Proteins ATG5 and Beclin 1 with Acute Myocardial Infarction in a Case-Control Study

Grazide,

Ruidavets,

Martinet

et al. 2024

Cardiology

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“…The findings presented herein suggest that reversal of physiological cardiac hypertrophy in pythons and mammals is accomplished through a similar strategy. While it is commonly believed that pathological remodeling is irreversible, we have previously shown that regression of pathological hypertrophy can occur in mice and humans and is associated with improved cardiac function and activation of autophagy 36,37 . However, it is not known whether FoxO1 mediates the regression of hypertrophy in these settings.…”

Section: Discussionmentioning

confidence: 88%

A Conserved Mechanism of Cardiac Hypertrophy Regression through FoxO1

Martin,

Hunt,

Langer

et al. 2024

Preprint

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The heart is a highly plastic organ that responds to diverse stimuli to modify form and function. The molecular mechanisms of adaptive physiological cardiac hypertrophy are well-established; however, the regulation of hypertrophy regression is poorly understood. To identify molecular features of regression, we studied Burmese pythons which experience reversible cardiac hypertrophy following large, infrequent meals. Using multi-omics screens followed by targeted analyses, we found forkhead box protein O1 (FoxO1) transcription factor signaling, and downstream autophagy activity, were downregulated during hypertrophy, but re-activated with regression. To determine whether these events were mechanistically related to regression, we established an in vitro platform of cardiomyocyte hypertrophy and regression from treatment with fed python plasma. FoxO1 inhibition prevented regression in this system, while FoxO1 activation reversed fed python plasma-induced hypertrophy in an autophagy-dependent manner. We next examined whether FoxO1 was implicated in mammalian models of reversible hypertrophy from exercise and pregnancy and found that in both cases FoxO1 was activated during regression. In these models, as in pythons, activation of FoxO1 was associated with increased expression FoxO1 target genes involved in autophagy. Taken together, our findings suggest FoxO1-dependent autophagy is a conserved mechanism for regression of physiological cardiac hypertrophy across species.

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Regression of postprandial cardiac hypertrophy in burmese pythons is mediated by FoxO1

Martin,

Hunt,

Langer

et al. 2024

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

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As ambush-hunting predators that consume large prey after long intervals of fasting, Burmese pythons evolved with unique adaptations for modulating organ structure and function. Among these is cardiac hypertrophy that develops within three days following a meal (Andersen et al., 2005, Secor, 2008), which we previously showed was initiated by circulating growth factors (Riquelme et al., 2011). Postprandial cardiac hypertrophy in pythons also rapidly regresses with subsequent fasting (Secor, 2008); however, the molecular mechanisms that regulate the dynamic cardiac remodeling in pythons during digestion are largely unknown. In this study, we employed a multiomics approach coupled with targeted molecular analyses to examine remodeling of the python ventricular transcriptome and proteome throughout digestion. We found that forkhead box protein O1 (FoxO1) signaling was suppressed prior to hypertrophy development and then activated during regression, which coincided with decreased and then increased expression, respectively, of FoxO1 transcriptional targets involved in proteolysis. To define the molecular mechanistic role of FoxO1 in hypertrophy regression, we used cultured mammalian cardiomyocytes treated with postfed python plasma. Hypertrophy regression both in pythons and in vitro coincided with activation of FoxO1-dependent autophagy; however, the introduction of a FoxO1-specific inhibitor prevented both regression of cell size and autophagy activation. Finally, to determine whether FoxO1 activation could induce regression, we generated an adenovirus expressing a constitutively active FoxO1. FoxO1 activation was sufficient to prevent and reverse postfed plasma-induced hypertrophy, which was partially prevented by autophagy inhibition. Our results indicate that modulation of FoxO1 activity contributes to the dynamic ventricular remodeling in postprandial Burmese pythons.

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Assessment of Autophagy Markers Suggests Increased Activity Following LVAD Therapy

Cited by 5 publications

References 33 publications

Association of Circulating Autophagy Proteins ATG5 and Beclin 1 with Acute Myocardial Infarction in a Case-Control Study

Association of Circulating Autophagy Proteins ATG5 and Beclin 1 with Acute Myocardial Infarction in a Case-Control Study

A Conserved Mechanism of Cardiac Hypertrophy Regression through FoxO1

Regression of postprandial cardiac hypertrophy in burmese pythons is mediated by FoxO1

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