Mutant ANP induces mitochondrial and ion channel remodeling in a human iPSC–derived atrial fibrillation model

Ly, Olivia T; Hanna, Calvin; Brown, Grace E.; Luan, Hong; Wang, Xinge; Han, Yong Duk; Pavel, Mahmud Arif; Sridhar, Arvind; Maienschein‐Cline, Mark; Chalazan, Brandon; Ong, Sang-Ging; Abdelhady, Khaled; Massad, Malek G.; Rizkallah, L.; Rehman, Jalees; Khetani, Salman R.; Darbar, Dawood

doi:10.1172/jci.insight.155640

Cited by 16 publications

(20 citation statements)

References 62 publications

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“…The iPSC-aCMs in PC showed increased OCR compared to RM, including spare respiratory capacity, ATP production, maximum respiration, and basal respiration, which is a hallmark of maturation as adult CMs rely heavily on oxidative phosphorylation rather than glycolysis ( 30 ). Protein expression of mitochondrial complexes I, II, III, and V (involved in oxidative phosphorylation) were fairly similar across both PC and RM, likely due to the inclusion of fatty acids (FAs) and TID [T3, insulin-like growth factor-1 (IGF-1), dexamethasone] soluble factors in the culture medium, which we have previously shown to improve the metabolic maturation of iPSC-aCMs in RM as well ( 54 ). Overall, our results suggest that the greater metabolic maturation of iPSC-aCMs in PC compared to RM may be due to enhanced ATP production and utilization by closely aligned elongated mitochondria and organized sarcomeres.…”

Section: Discussionmentioning

confidence: 99%

“…For even distribution of iPSC-aCMs on the FN micropatterns, the plate was shaken every 20 min for 3 hours. After 48 hours, CFs were passaged and resuspended in media containing 2% FBS, P/S, and additional factors that have been shown to lead to CM maturation, specifically 100 nM T3 (MilliporeSigma), IGF-1 (100 ng/ml; PeproTech, East Windsor, NJ), 1 μM dexamethasone (BioGems, Westlake Village, CA) ( 54 , 66 ), herein referred collectively as “TID,” and FAs (100 μM oleic acid and 50 μM palmitic acid, MilliporeSigma) complexed with BSA, herein referred to as “CMM-TID/FA” media. Before CF seeding, the micropatterned iPSC-aCMs were rinsed with CMM.…”

Section: Methodsmentioning

confidence: 99%

“…Four days before analysis, iPSC-aCMs were sorted via magnetic activated cell sorting (MACS) and replated onto FN-coated Seahorse XFe96 cell culture microplates at a density of 40,000 cells per well with media changes every other day. The assay was performed as described previously ( 54 ). Briefly, culture medium on cells was changed to 100 μl per well of bicarbonate-free RPMI 1640 (Agilent Technologies) and incubated in a non-CO 2 incubator for 1 hour at 37°C.…”

Section: Methodsmentioning

confidence: 99%

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Engineered cocultures of iPSC-derived atrial cardiomyocytes and atrial fibroblasts for modeling atrial fibrillation

Brown,

Han,

Michell

et al. 2024

Sci. Adv.

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Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia treatable with antiarrhythmic drugs; however, patient responses remain highly variable. Human induced pluripotent stem cell–derived atrial cardiomyocytes (iPSC-aCMs) are useful for discovering precision therapeutics, but current platforms yield phenotypically immature cells and are not easily scalable for high-throughput screening. Here, primary adult atrial, but not ventricular, fibroblasts induced greater functional iPSC-aCM maturation, partly through connexin-40 and ephrin-B1 signaling. We developed a protein patterning process within multiwell plates to engineer patterned iPSC-aCM and atrial fibroblast coculture (PC) that significantly enhanced iPSC-aCM structural, electrical, contractile, and metabolic maturation for 6+ weeks compared to conventional mono-/coculture. PC displayed greater sensitivity for detecting drug efficacy than monoculture and enabled the modeling and pharmacological or gene editing treatment of an AF-like electrophysiological phenotype due to a mutated sodium channel. Overall, PC is useful for elucidating cell signaling in the atria, drug screening, and modeling AF.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Engineered cocultures of iPSC-derived atrial cardiomyocytes and atrial fibroblasts for modeling atrial fibrillation

Brown,

Han,

Michell

et al. 2024

Sci. Adv.

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“…A long-term proBNP peptide gene delivery exerted an anti-hypertrophic effect and improved both systolic and diastolic function in the spontaneously hypertensive rat [ 55 ]. An NPPA mutation was associated with the enhanced expression and function of a cardiac potassium channel and to mitochondrial electron transport chain dysfunction, resulting in an electrophysiological substrate for atrial fibrillation [ 56 , 57 ]. Moreover, ANPs were recently discovered to regulate cardiac autophagy, reducing the cellular quote of damaged cells and organelles, and finally protecting the heart from ischemic insult [ 58 ].…”

Section: Natriuretic Peptide Receptorsmentioning

confidence: 99%

Natriuretic Peptides: It Is Time for Guided Therapeutic Strategies Based on Their Molecular Mechanisms

Gallo

Rubattu

Autore

et al. 2023

IJMS

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Natriuretic peptides (NPs) are the principal expression products of the endocrine function of the heart. They exert several beneficial effects, mostly mediated through guanylate cyclase-A coupled receptors, including natriuresis, diuresis, vasorelaxation, blood volume and blood pressure reduction, and regulation of electrolyte homeostasis. As a result of their biological functions, NPs counterbalance neurohormonal dysregulation in heart failure and other cardiovascular diseases. NPs have been also validated as diagnostic and prognostic biomarkers in cardiovascular diseases such as atrial fibrillation, coronary artery disease, and valvular heart disease, as well as in the presence of left ventricular hypertrophy and severe cardiac remodeling. Serial measurements of their levels may be used to contribute to more accurate risk stratification by identifying patients who are more likely to experience death from cardiovascular causes, heart failure, and cardiac hospitalizations and to guide tailored pharmacological and non-pharmacological strategies with the aim to improve clinical outcomes. On these premises, multiple therapeutic strategies based on the biological properties of NPs have been attempted to develop new targeted cardiovascular therapies. Apart from the introduction of the class of angiotensin receptor/neprilysin inhibitors to the current management of heart failure, novel promising molecules including M-atrial natriuretic peptide (a novel atrial NP-based compound) have been tested for the treatment of human hypertension with promising results. Moreover, different therapeutic strategies based on the molecular mechanisms involved in NP regulation and function are under development for the management of heart failure, hypertension, and other cardiovascular conditions.

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“…As part of the cardiac endocrine system, ANP promotes vasodilation in peripheral vessels and natriuresis in the kidney to preserve normal blood volume and pressure. Moreover, ANP acts in the heart to maintain cellular structure and function [ 6 , 7 ] and in non-cardiac tissues to regulate inflammation [ 8 , 9 , 10 ] and vascular remodeling [ 11 , 12 , 13 ]. Polymorphisms in the NPPA gene, encoding the ANP precursor, have been associated with blood pressure levels [ 14 ] and cardiovascular disorders [ 15 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

Corin Deficiency Alters Adipose Tissue Phenotype and Impairs Thermogenesis in Mice

Zhang

Zhou

et al. 2022

Biology

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Atrial natriuretic peptide (ANP) is a key regulator in body fluid balance and cardiovascular biology. In addition to its role in enhancing natriuresis and vasodilation, ANP increases lipolysis and thermogenesis in adipose tissue. Corin is a protease responsible for ANP activation. It remains unknown if corin has a role in regulating adipose tissue function. Here, we examined adipose tissue morphology and function in corin knockout (KO) mice. We observed increased weights and cell sizes in white adipose tissue (WAT), decreased levels of uncoupling protein 1 (Ucp1), a brown adipocyte marker in WAT and brown adipose tissue (BAT), and suppressed thermogenic gene expression in BAT from corin KO mice. At regular room temperature, corin KO and wild-type mice had similar metabolic rates. Upon cold exposure at 4 °C, corin KO mice exhibited impaired thermogenic responses and developed hypothermia. In BAT from corin KO mice, the signaling pathway of p38 mitogen-activated protein kinase, peroxisome proliferator-activated receptor c coactivator 1a, and Ucp1 was impaired. In cell culture, ANP treatment increased Ucp1 expression in BAT-derived adipocytes from corin KO mice. These data indicate that corin mediated-ANP activation is an important hormonal mechanism in regulating adipose tissue function and body temperature upon cold exposure in mice.

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Mutant ANP induces mitochondrial and ion channel remodeling in a human iPSC–derived atrial fibrillation model

Cited by 16 publications

References 62 publications

Engineered cocultures of iPSC-derived atrial cardiomyocytes and atrial fibroblasts for modeling atrial fibrillation

Engineered cocultures of iPSC-derived atrial cardiomyocytes and atrial fibroblasts for modeling atrial fibrillation

Natriuretic Peptides: It Is Time for Guided Therapeutic Strategies Based on Their Molecular Mechanisms

Corin Deficiency Alters Adipose Tissue Phenotype and Impairs Thermogenesis in Mice

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