Reversibility of etomidate-induced contractile arrest through activation of myocardial autophagy
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA873692 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR21201628_1.fastq.gz | Fastqsanger.gz | |||
| SRR21201628_2.fastq.gz | Fastqsanger.gz | |||
| SRR21201629_1.fastq.gz | Fastqsanger.gz | |||
| SRR21201629_2.fastq.gz | Fastqsanger.gz | |||
| SRR21201630_1.fastq.gz | Fastqsanger.gz |
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Project description:Anesthetic management of heart failure patients undergoing noncardiac surgery remains challenging due to cardiac suppressive properties of anesthetics. Due to varying electrophysiological properties, small and large animals are not good models for studying human myocardial anesthetic responses. Here we use hypertrophic (HCM), dilated (DCM) and healthy human induced pluripotent stem cells derived cardiomyocytes (hiPSC-CMs) to evaluate the cardiac suppression of propofol and etomidate. We demonstrate that propofol and etomidate act through GABAA receptors and contractile inhibition can occur without cell-cell junction. At supraphysiological dosage (100mM), we discovered that cardiac suppression induced by etomidate is reversible while propofol is not. Using transcriptome profiling, we uncover that etomidate was capable of inducing autophagy, likely through induction of cytosolic calcium. Lack of autophagy induction in propofol treated cardiomyocytes were associated with increased apoptosis. Together, we provide the robustness of using hiPSC-CMs as an in vitro cardiotoxicity platform for anesthetics. To delineate how etomidate confers cardioprotection during contraction inhibition, we performed transcriptome profiling on DCM hiPSC-CMs treated with either 10 μM propofol, 10 μM etomidate or DMSO control.
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Project description:Impaired myocardial contractile function is a hallmark of heart failure (HF) which may present under resting conditions and/or during physiological stress. Previous studies reported that high fat feeding in HF is associated with improved myocardial contractile function at baseline. Our goal was to determine whether myocardial function is compromised in response to physiological stress and to evaluate the global gene expression profile of rats fed high dietary fat following infarction. Male Wistar rats underwent ligation or sham surgery and were fed normal (10% kcal fat) (SHAM+NC, HF+NC) or high fat (60% kcal saturated fat) (SHAM+SAT, HF+SAT) for 8 weeks. Myocardial contractile function was assessed using a Millar pressure-volume (PV) conductance catheter at baseline, during inferior vena caval occlusions and dobutamine (DOB) stress. Steady state indices of systolic function, left ventricular (LV)+dP/dtmax, stroke work and maximal power were increased in HF+SAT vs HF+NC; HF+NC were reduced vs SHAM+NC. Preload-recruitable measures of contractility [end systolic PV relationship, maximal elastance, preload recruitable SW and peak+dP/dtmax to end diastolic volume] were decreased in HF+NC but not HF+SAT. β-adrenergic responsiveness (delta-LV+dP/dtmax and delta-cardiac output DOB 0-10 µg•kg-1•min-1) was reduced in HF, but high fat feeding did not further impact contractile reserve in HF. Contractile reserve was reduced by high fat in SHAM+SAT. Microarray gene expression analysis reveals the majority of significantly altered pathways identified to contain multiple gene targets correspond to cell signaling pathways and energy metabolism. These findings suggest that high saturated fat improves myocardial function at rest and during physiological stress in infarcted hearts, but may negatively impact contractile reserve under non-pathological conditions. Furthermore, high fat feeding-induced alterations in gene expression related to energy metabolism and specific signaling pathways reveal promising targets through which high saturated fat potentially mediates cardioprotection in heart failure/LV dysfunction. Comparison of gene expression in heart failure or sham surgery hearts exposed to saturated or normal diets. Male Wistar rats (300-350g) were maintained on a reverse light-dark cycle and all procedures were done 3-6 hours into the dark phase cycle to synchronize with the normal active state of the rodents. Rats were randomly assigned to receive either a sham-operation (SH) or coronary ligation to induce cardiac dysfunction (HF). Heart failure was induced by ligating the left main coronary artery. Following surgery, rats were immediately fed either a normal rodent chow (NC) or a high saturated fat chow (SAT) with 60% caloric content derived from fat (25% palmitic, 33% stearic, 33% oleic acid, Research Diets).
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Project description:Impaired myocardial contractile function is a hallmark of heart failure (HF) which may present under resting conditions and/or during physiological stress. Previous studies reported that high fat feeding in HF is associated with improved myocardial contractile function at baseline. Our goal was to determine whether myocardial function is compromised in response to physiological stress and to evaluate the global gene expression profile of rats fed high dietary fat following infarction. Male Wistar rats underwent ligation or sham surgery and were fed normal (10% kcal fat) (SHAM+NC, HF+NC) or high fat (60% kcal saturated fat) (SHAM+SAT, HF+SAT) for 8 weeks. Myocardial contractile function was assessed using a Millar pressure-volume (PV) conductance catheter at baseline, during inferior vena caval occlusions and dobutamine (DOB) stress. Steady state indices of systolic function, left ventricular (LV)+dP/dtmax, stroke work and maximal power were increased in HF+SAT vs HF+NC; HF+NC were reduced vs SHAM+NC. Preload-recruitable measures of contractility [end systolic PV relationship, maximal elastance, preload recruitable SW and peak+dP/dtmax to end diastolic volume] were decreased in HF+NC but not HF+SAT. β-adrenergic responsiveness (delta-LV+dP/dtmax and delta-cardiac output DOB 0-10 µg•kg-1•min-1) was reduced in HF, but high fat feeding did not further impact contractile reserve in HF. Contractile reserve was reduced by high fat in SHAM+SAT. Microarray gene expression analysis reveals the majority of significantly altered pathways identified to contain multiple gene targets correspond to cell signaling pathways and energy metabolism. These findings suggest that high saturated fat improves myocardial function at rest and during physiological stress in infarcted hearts, but may negatively impact contractile reserve under non-pathological conditions. Furthermore, high fat feeding-induced alterations in gene expression related to energy metabolism and specific signaling pathways reveal promising targets through which high saturated fat potentially mediates cardioprotection in heart failure/LV dysfunction.
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