scholarly journals Targeting mir128-3p alleviates myocardial insulin resistance and prevents ischemia-induced heart failure

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Andrea Ruiz-Velasco ◽  
Min Zi ◽  
Susanne S Hille ◽  
Tayyiba Azam ◽  
Namrita Kaur ◽  
...  
Keyword(s):  
Heart Failure ◽  
Insulin Resistance ◽  
Cardiac Dysfunction ◽  
Cardiac Injury ◽  
Induced Pluripotent Stem Cell ◽  
Mitogen Activated Protein Kinase ◽  
Rat Cardiomyocytes ◽  
Functional Studies ◽  
Mitogen Activated Protein ◽  
Myocardial Insulin Resistance

Myocardial insulin resistance contributes to heart failure in response to pathological stresses, therefore, a therapeutic strategy to maintain cardiac insulin pathways requires further investigation. We demonstrated that insulin receptor substrate 1 (IRS1) was reduced in failing mouse hearts post-myocardial infarction (MI) and failing human hearts. The mice manifesting severe cardiac dysfunction post-MI displayed elevated mir128-3p in the myocardium. Ischemia-upregulated mir128-3p promoted Irs1 degradation. Using rat cardiomyocytes and human-induced pluripotent stem cell-derived cardiomyocytes, we elucidated that mitogen-activated protein kinase 7 (MAPK7, also known as ERK5)-mediated CCAAT/enhancer-binding protein beta (CEBPβ) transcriptionally represses mir128-3p under hypoxia. Therapeutically, functional studies demonstrated gene therapy-delivered cardiac-specific MAPK7 restoration or overexpression of CEBPβ impeded cardiac injury after MI, at least partly due to normalization of mir128-3p. Furthermore, inhibition of mir128-3p preserved Irs1 and ameliorated cardiac dysfunction post-MI. In conclusion, we reveal that targeting mir128-3p mitigates myocardial insulin resistance, thereafter slowing down the progression of heart failure post-ischemia.

scholarly journals COVID19-associated cardiomyocyte dysfunction, arrhythmias and the effect of Canakinumab

PLoS ONE ◽  
2021 ◽  
Vol 16 (8) ◽  
pp. e0255976
Author(s):  
Sanzio Dimai ◽  
Lukas Semmler ◽  
Ashok Prabhu ◽  
Harald Stachelscheid ◽  
Judith Huettemeister ◽  
...  
Keyword(s):  
Cardiac Dysfunction ◽  
Therapeutic Potential ◽  
Cardiac Injury ◽  
Induced Pluripotent Stem Cell ◽  
Rat Cardiomyocytes ◽  
Excitation Contraction Coupling ◽  
Contraction Coupling ◽  
Induced Pluripotent

Background Cardiac injury associated with cytokine release frequently occurs in SARS-CoV-2 mediated coronavirus disease (COVID19) and mortality is particularly high in these patients. The mechanistic role of the COVID19 associated cytokine-storm for the concomitant cardiac dysfunction and associated arrhythmias is unclear. Moreover, the role of anti-inflammatory therapy to mitigate cardiac dysfunction remains elusive. Aims and methods We investigated the effects of COVID19-associated inflammatory response on cardiac cellular function as well as its cardiac arrhythmogenic potential in rat and induced pluripotent stem cell derived cardiomyocytes (iPS-CM). In addition, we evaluated the therapeutic potential of the IL-1β antagonist Canakinumab using state of the art in-vitro confocal and ratiometric high-throughput microscopy. Results Isolated rat ventricular cardiomyocytes were exposed to control or COVID19 serum from intensive care unit (ICU) patients with severe ARDS and impaired cardiac function (LVEF 41±5%; 1/3 of patients on veno-venous extracorporeal membrane oxygenation; CK 154±43 U/l). Rat cardiomyocytes showed an early increase of myofilament sensitivity, a decrease of Ca2+ transient amplitudes and altered baseline [Ca2+] upon exposure to patient serum. In addition, we used iPS-CM to explore the long-term effect of patient serum on cardiac electrical and mechanical function. In iPS-CM, spontaneous Ca2+ release events were more likely to occur upon incubation with COVID19 serum and nuclear as well as cytosolic Ca2+ release were altered. Co-incubation with Canakinumab had no effect on pro-arrhythmogenic Ca2+ release or Ca2+ signaling during excitation-contraction coupling, nor significantly influenced cellular automaticity. Conclusion Serum derived from COVID19 patients exerts acute cardio-depressant and chronic pro-arrhythmogenic effects in rat and iPS-derived cardiomyocytes. Canakinumab had no beneficial effect on cellular Ca2+ signaling during excitation-contraction coupling. The presented method utilizing iPS-CM and in-vitro Ca2+ imaging might serve as a novel tool for precision medicine. It allows to investigate cytokine related cardiac dysfunction and pharmacological approaches useful therein.

scholarly journals Hepatic Mitogen-Activated Protein Kinase Phosphatase 1 Selectively Regulates Glucose Metabolism and Energy Homeostasis

2014 ◽  
Vol 35 (1) ◽  
pp. 26-40 ◽  
Author(s):  
Ahmed Lawan ◽  
Lei Zhang ◽  
Florian Gatzke ◽  
Kisuk Min ◽  
Michael J. Jurczak ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Protein Kinase ◽  
Glucose Metabolism ◽  
Energy Homeostasis ◽  
Mitogen Activated Protein Kinase ◽  
Hepatic Insulin Resistance ◽  
Fibroblast Growth Factor 21 ◽  
High Fat ◽  
Mitogen Activated Protein ◽  
Fat Feeding

The liver plays a critical role in glucose metabolism and communicates with peripheral tissues to maintain energy homeostasis. Obesity and insulin resistance are highly associated with nonalcoholic fatty liver disease (NAFLD). However, the precise molecular details of NAFLD remain incomplete. The p38 mitogen-activated protein kinase (MAPK) and c-Jun NH2-terminal kinase (JNK) regulate liver metabolism. However, the physiological contribution of MAPK phosphatase 1 (MKP-1) as a nuclear antagonist of both p38 MAPK and JNK in the liver is unknown. Here we show that hepatic MKP-1 becomes overexpressed following high-fat feeding. Liver-specific deletion of MKP-1 enhances gluconeogenesis and causes hepatic insulin resistance in chow-fed mice while selectively conferring protection from hepatosteatosis upon high-fat feeding. Further, hepatic MKP-1 regulates both interleukin-6 (IL-6) and fibroblast growth factor 21 (FGF21). Mice lacking hepatic MKP-1 exhibit reduced circulating IL-6 and FGF21 levels that were associated with impaired skeletal muscle mitochondrial oxidation and susceptibility to diet-induced obesity. Hence, hepatic MKP-1 serves as a selective regulator of MAPK-dependent signals that contributes to the maintenance of glucose homeostasis and peripheral tissue energy balance. These results also demonstrate that hepatic MKP-1 overexpression in obesity is causally linked to the promotion of hepatosteatosis.

scholarly journals Angiotensin II–Triggered p44/42 Mitogen-Activated Protein Kinase Mediates Sympathetic Excitation in Heart Failure Rats

Hypertension ◽  
2008 ◽  
Vol 52 (2) ◽  
pp. 342-350 ◽  
Author(s):  
Shun-Guang Wei ◽  
Yang Yu ◽  
Zhi-Hua Zhang ◽  
Robert M. Weiss ◽  
Robert B. Felder
Keyword(s):  
Heart Failure ◽  
Angiotensin Ii ◽  
Protein Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein

scholarly journals Comparison of the protective effects of steamed and cooked broccolis on ischaemia–reperfusion-induced cardiac injury

2009 ◽  
Vol 103 (6) ◽  
pp. 815-823 ◽  
Author(s):  
Subhendu Mukherjee ◽  
Istvan Lekli ◽  
Diptarka Ray ◽  
Hiranmoy Gangopadhyay ◽  
Utpal Raychaudhuri ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Injury ◽  
Mitogen Activated Protein Kinase ◽  
Related Factor ◽  
Protective Effects ◽  
Extracellular Signal Regulated Kinase ◽  
Redox Signalling ◽  
Ischaemia Reperfusion ◽  
Extracellular Signal ◽  
Mitogen Activated Protein

Recently, broccoli, a vegetable of the Brassica family, has been found to protect the myocardium from ischaemic reperfusion injury through the redox signalling of sulphoraphane, which is being formed from glucosinolate present in this vegetable. Since cooked broccoli loses most of its glucosinolate, we assumed that fresh broccoli could be a superior cardioprotective agent compared to cooked broccoli. To test this, two groups of rats were fed with fresh (steamed) broccoli or cooked broccoli for 30 d, while a third group was given vehicle only for the same period of time. After 30 d, all the rats were sacrificed, and the isolated working hearts were subjected to 30 min ischaemia followed by 2 h of reperfusion. Both cooked and steamed broccolis displayed significantly improved post-ischaemic ventricular function and reduced myocardial infarction and cardiomyocyte apoptosis compared to control, but steamed broccoli showed superior cardioprotective abilities compared with the cooked broccoli. Corroborating with these results, both cooked and steamed broccolis demonstrated significantly enhanced induction of the survival signalling proteins including Bcl2, Akt, extracellular signal-regulated kinase 1/2, haemoxygenase-1, NFE2 related factor 2, superoxide dismutase (SOD1) and SOD2 and down-regulation of the proteins (e.g. Bax, c-Jun N-terminal kinase, p38 mitogen-activated protein kinase) of the death signalling pathway, steamed broccoli displaying superior results over its cooked counterpart. The expressions of proteins of the thioredoxin (Trx) superfamily including Trx1 and its precursor sulphoraphane, Trx2 and Trx reductase, were enhanced only in the steamed broccoli group. The results of the present study documented superior cardioprotective properties of the steamed broccoli over cooked broccoli because of the ability of fresh broccoli to perform redox signalling of Trx.

Akt is a critical node of acute myocardial insulin resistance and cardiac dysfunction after cardiopulmonary bypass

Life Sciences ◽  
2019 ◽  
Vol 234 ◽  
pp. 116734 ◽  
Author(s):  
Zhifa Wang ◽  
Yunya Wang ◽  
Yuehu Han ◽  
Qiang Yin ◽  
Sheng Hu ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Cardiopulmonary Bypass ◽  
Cardiac Dysfunction ◽  
Critical Node ◽  
Myocardial Insulin Resistance

scholarly journals Overfeeding during Lactation in Rats is Associated with Cardiovascular Insulin Resistance in the Short-Term

Nutrients ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 549 ◽  
Author(s):  
Daniel González-Hedström ◽  
Lucía Guerra-Menéndez ◽  
Antonio Tejera-Muñoz ◽  
Sara Amor ◽  
María de la Fuente-Fernández ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Glucose Transporter ◽  
Mitogen Activated Protein Kinase ◽  
Lactation Period ◽  
Cardiovascular Comorbidities ◽  
Rat Pups ◽  
Mitogen Activated Protein ◽  
Phosphoinositide 3 Kinase ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

Childhood obesity is associated with metabolic and cardiovascular comorbidities. The development of these alterations may have its origin in early life stages such as the lactation period through metabolic programming. Insulin resistance is a common complication in obese patients and may be responsible for the cardiovascular alterations associated with this condition. This study analyzed the development of cardiovascular insulin resistance in a rat model of childhood overweight induced by overfeeding during the lactation period. On birth day, litters were divided into twelve (L12) or three pups per mother (L3). Overfed rats showed a lower increase in myocardial contractility in response to insulin perfusion and a reduced insulin-induced vasodilation, suggesting a state of cardiovascular insulin resistance. Vascular insulin resistance was due to decreased activation of phosphoinositide 3-kinase (PI3K)/Akt pathway, whereas cardiac insulin resistance was associated with mitogen-activated protein kinase (MAPK) hyperactivity. Early overfeeding was also associated with a proinflammatory and pro-oxidant state; endothelial dysfunction; decreased release of nitrites and nitrates; and decreased gene expression of insulin receptor (IR), glucose transporter-4 (GLUT-4), and endothelial nitric oxide synthase (eNOS) in response to insulin. In conclusion, overweight induced by lactational overnutrition in rat pups is associated with cardiovascular insulin resistance that could be related to the cardiovascular alterations associated with this condition.

scholarly journals Targeted Inhibition of p38 Mitogen-activated Protein Kinase Antagonizes Cardiac Injury and Cell Death Following Ischemia-Reperfusionin Vivo

2004 ◽  
Vol 279 (15) ◽  
pp. 15524-15530 ◽  
Author(s):  
Robert A. Kaiser ◽  
Orlando F. Bueno ◽  
Daniel J. Lips ◽  
Pieter A. Doevendans ◽  
Fred Jones ◽  
...  
Keyword(s):  
Cell Death ◽  
Protein Kinase ◽  
Cardiac Injury ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein ◽  
Targeted Inhibition
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