The MAP4 Projection Domain Accelerates Hypoxia-Induced Mitophagy Disruption through LIR Motif in Cardiomyocytes

2021 ◽  
Author(s):  
Yuesheng Huang ◽  
Yanhai Feng ◽  
Qiong Zhang ◽  
Lingfei Li ◽  
Junhui Zhang ◽  
...  
Keyword(s):  
Heart Failure ◽  
Myocardial Hypertrophy ◽  
Myocardial Damage ◽  
Autophagic Flux ◽  
Ischemic Heart Failure ◽  
Detailed Mechanism ◽  
Mitochondrial Translocation ◽  
Promising Therapeutic Target ◽  
Projection Domain ◽  
Lir Motif

Abstract Previously, we and other investigators have demonstrated that phosphorylated microtubule-associated protein 4 (p-MAP4) impacts myocardial hypertrophy and ischemic heart failure. However, the detailed mechanism behind this remains under elucidated. Published studies have suggested that impaired mitophagy contributes to hypoxia-induced myocardial damage, hence the involvement of p-MAP4 in mitophagy in cardiomyocytes was investigated. The results herein revealed that there was increased degradation of mitochondria, accumulated mitophagosomes and disrupted autophagic flux in both neonatal and adult ones of MAP4-knockin (KI) mice. This indicated that p-MAP4 persistently degraded mitochondria through activating mitophagy. Next, Tom70 was found as the importer of p-MAP4 in the context of mitochondrial translocation. And, the LC3-interacting region (LIR) motif (47–50aa) caused p-MAP4-induced mitochondrial engulfment, and the ubiquitin-interacting motif (UIM) domain determined the characteristics of p-MAP4-induced mitophagosomes, which were structure and membrane potential-independent. Moreover, p-MAP4 enhanced hypoxia-induced mitophagic flux impairment, and p-MAP4 LIR (47–50aa) mutation decreased hypoxia-induced autophagy both in MAP4 knockout and wildtype cardiomyocytes. Overall, this study identified that p-MAP4 as a novel mediator and cargo receptor in mitophagy, and that the degradation of the MAP4 PJ domain as a promising therapeutic target for improving the cardiac function of hypoxia-related heart failure or cardiac remodelling.

scholarly journals Impaired mitochondrial biogenesis is a common feature to myocardial hypertrophy and end-stage ischemic heart failure

2016 ◽  
Vol 25 (2) ◽  
pp. 103-112 ◽  
Author(s):  
Annalinda Pisano ◽  
Bruna Cerbelli ◽  
Elena Perli ◽  
Maria Pelullo ◽  
Valentina Bargelli ◽  
...  
Keyword(s):  
Heart Failure ◽  
Mitochondrial Biogenesis ◽  
Myocardial Hypertrophy ◽  
Ischemic Heart ◽  
Ischemic Heart Failure ◽  
End Stage

Abstract 250: Differential Role of Autophagy in Idiopathic versus Ischemic Heart Failure in Humans

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Antoinette Bugyei-Twum ◽  
Krishna K Singh ◽  
Filio Billia ◽  
Kim A Connelly
Keyword(s):  
Heart Failure ◽  
Ischemia Reperfusion ◽  
Fold Increase ◽  
Left Ventricular ◽  
Beclin 1 ◽  
Ischemic Heart ◽  
Autophagic Flux ◽  
Ischemic Heart Failure ◽  
Autophagic Activity

Background: Autophagy is an evolutionary conserved process that plays a key role in a variety of physiological and pathological processes. Despite its beneficial role, excessive/insufficient autophagic activity is known to contribute to the pathogenesis of cardiovascular disorders, including ischemia/reperfusion injury and heart failure. However, the differential role of autophagy in idiopathic versus ischemic heart failure remains unknown. Methods: To investigate the role of autophagy and associated apoptosis in idiopathic versus ischemic heart failure, we obtained LV myocardium biopsies from healthy controls (via 3 commercial sources), and from 10 patients with idiopathic and ischemic end-stage heart failure before the insertion of a left ventricular assist devise. The expression of inducers/markers of autophagy (mTOR, phospho-mTOR, LC3-I/II, p62, Beclin-1, autophagy-related genes ATG4B/ATG5) and apoptosis (Bcl-2 and caspase-3) were assessed at the transcript and protein level using quantitative RT-PCR and Western blotting. Results: Autophagy was activated in both idiopathic and ischemic heart failure in comparison to control, as confirmed by a significant reduction in mTOR expression/activation and a 3.4-fold and 2.2-fold increase in LC3 II/I ratio, respectively. An increase in apoptosis, marked by increased caspase3 and Bcl2 expression, was also observed in both groups in comparison to control. Interestingly, autophagy activity—marked by decreased mTOR expression/activation, increased ATG4B, ATG5, and Beclin-1—was significantly higher in idiopathic heart failure, when compared to ischemic heart failure. While we observed increased autophagic activity in idiopathic heart failure, p62 expression was also significantly increased in this group (2.8-fold increase; p<0.05), demonstrating an impairment of autophagic flux in idiopathic versus ischemic heart failure. Conclusions: For the first time, we provide a direct comparision of autophagy and apoptosis in idiopathic versus ischemic heart failure. Our data, demonstrating an excessive yet insufficient autophagic activity in idiopathic heart failure, suggests a differential role of autophagy apoptosis in idiopathic versus ischemia-related heart failure.

scholarly journals The research of neurohormonal biomarkers in arterial hypertension diagnosis in adolescents

2016 ◽  
Vol 63 (2) ◽  
pp. 140-147
Author(s):  
Victoria Grosu ◽  
◽  
Victoria Melnicov ◽  
Keyword(s):  
Heart Failure ◽  
Chronic Heart Failure ◽  
Arterial Hypertension ◽  
Myocardial Hypertrophy ◽  
Myocardial Damage ◽  
Control Group ◽  
Hemodynamic Parameters ◽  
Biochemical Tests ◽  
Hypertension Diagnosis

Arterial hypertension (AHT) is currently considered one of the most common pathologies of the cardiovascular system and one of the risk factors of atherosclerosis and chronic myocardial dysfunctions. Essential hypertension is accompanied by metabolic disorders, hypercatecholaminemia, hypertriglyceridemia, hyperinsulinemia, excessive fat storage in adipocytes in obese patients as well as other factors. To assess the degree and prognosis of arterial hypertension, it is important to use early diagnosis, first of all the signs of heart remodeling, metabolic and neurohormonal disorders, and changes in the arterial wall. Objectives of the study. Indices evaluation of neurohormonal biomarkers in arterial hypertension diagnosis in adolescents. Material and methods. The hemodynamic parameters of cardiac performance and neurohormonal biomarkers have been evaluated in this study of 113 children, divided in two groups. The first group included 52 patients, having chronic heart failure secondary to arterial hypertension and the second control group included 85 children. Obtained results. The EcoCG parameters in patients with arterial hypertension detected left myocardial hypertrophy and the septum myocardial hypertrophy, and the modification of the LVEF, LVSF. The determination of specific biochemical tests assessing myocardial damage biomarkers in patients with congestive heart failure secondary to arterial hypertension confirmed a statistically significant increase in serum content epinephrine in comparison with the control group (p<0.001), of the conclusive norepinephrine the control (p<0.05) and increase in urine content catecholamine in activity significance compared to the control group (p<0.001), with further increase concentration level in the dynamic therapy (p<0.001). Conclusions. The investigation performed shows that the patients with chronic heart failure develop hypoxic and ischemic processes, that lead to modified of hemodynamic parameters and metabolic and neurohormonal biomarkers.

Estimation of the Safety of Intraoperative Fluid Therapy during Great Abdominal Surgery in Patients with Coronary Heart Disease

2020 ◽  
Vol 5 (5) ◽  
pp. 158-163
Author(s):  
V. I. Lysenko ◽  
◽  
E. A. Karpenko ◽  
Ya. V. Morozova
Keyword(s):  
Heart Failure ◽  
Coronary Heart Disease ◽  
Heart Disease ◽  
Fluid Therapy ◽  
Troponin I ◽  
Significant Proportion ◽  
Myocardial Damage ◽  
Enzyme Linked Immunosorbent Assay ◽  
Cardiac Complications ◽  
Fluid Regimen

The study of intraoperative fluid therapy tactics has been of great interest over the past few years, especially in people with concomitant coronary heart disease, as they make up a significant proportion of all surgical patients. The purpose of our study was to assess the risk of intraoperative myocardial damage in patients with concomitant coronary heart disease depending on the fluid regimen used based on monitoring of hemodynamic parameters, electrocardiogram and biomarkers of myocardial damage. Material and methods. The study involved 89 patients, who were divided into two groups depending on the tactics of intraoperative fluid therapy – restrictive and liberal. In order to detect cardiac complications at different stages, we assessed biomarkers of myocardial damage Troponin I, NT-proBNP by solid-phase enzyme-linked immunosorbent assay (ELISA). Results and discussion. Analysis of the obtained data showed that MINS (myocardial injury in noncardiac surgery) incidents were diagnosed in 5 patients (11.1%) in the first group and in 6 patients (13.6%) in the second. In patients of both groups there was an increase in NT-proBNP in the dynamics at all stages, and in the 2nd group, with a liberal regimen of intraoperative fluid therapy, it was more pronounced. It should be noted that the obtained values of NT-proBNP in all patients did not differ significantly from those allowed for this age group; such dynamics of NT-proBNP may indicate a relative risk of complications of liberal fluid therapy in patients with baseline heart failure. One of the important points when choosing the mode of fluid therapy in patients with high cardiac risk is the assessment of the initial volemic status and careful monitoring of water balance in the perioperative period with the desire for "zero" balance. The obtained dynamics of laboratory markers of myocardial damage indicates that in patients with a significant reduction in cardiac reserves compensated for heart failure, a restrictive fluid regimen is preferable, which is also confirmed by slight changes in the concentration of biomarkers. Conclusion. Thus, the study demonstrated the relative safety of selected fluid regimens in patients with concomitant coronary heart disease without signs of congestive heart failure

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