Dataset Information

A Computational Approach for Understanding the Interactions between Graphene Oxide and Nucleoside Diphosphate Kinase with Implications for Heart Failure.

ABSTRACT: During a heart failure, an increased content and activity of nucleoside diphosphate kinase (NDPK) in the sarcolemmal membrane is responsible for suppressing the formation of the second messenger cyclic adenosine monophosphate (cAMP)-a key component required for calcium ion homeostasis for the proper systolic and diastolic functions. Typically, this increased NDPK content lets the surplus NDPK react with a mutated G protein in the beta-adrenergic signal transduction pathway, thereby inhibiting cAMP synthesis. Thus, it is thus that inhibition of NDPK may cause a substantial increase in adenylate cyclase activity, which in turn may be a potential therapy for end-stage heart failure patients. However, there is little information available about the molecular events at the interface of NDPK and any prospective molecule that may potentially influence its reactive site (His118). Here we report a novel computational approach for understanding the interactions between graphene oxide (GO) and NDPK. Using molecular dynamics, it is found that GO interacts favorably with the His118 residue of NDPK to potentially prevent its binding with adenosine triphosphate (ATP), which otherwise would trigger the phosphorylation of the mutated G protein. Therefore, this will result in an increase in cAMP levels during heart failure.

SUBMITTER: Ray A

PROVIDER: S-EPMC5853690 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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A Computational Approach for Understanding the Interactions between Graphene Oxide and Nucleoside Diphosphate Kinase with Implications for Heart Failure.

Ray Anushka A Macwan Isaac I Singh Shrishti S Silwal Sushila S Patra Prabir P

Nanomaterials (Basel, Switzerland) 20180123 2

During a heart failure, an increased content and activity of nucleoside diphosphate kinase (NDPK) in the sarcolemmal membrane is responsible for suppressing the formation of the second messenger cyclic adenosine monophosphate (cAMP)-a key component required for calcium ion homeostasis for the proper systolic and diastolic functions. Typically, this increased NDPK content lets the surplus NDPK react with a mutated G protein in the beta-adrenergic signal transduction pathway, thereby inhibiting cA ...[more]

PMID: 29360759

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Project description:With an estimated 64.3 million cases worldwide, heart failure (HF) imposes an enormous burden on healthcare systems. Sudden death from arrhythmia is the major cause of mortality in HF patients. Computational modeling of the failing heart provides insights into mechanisms of arrhythmogenesis, risk stratification of patients, and clinical treatment. However, the lack of a clinically informed approach to model cardiac tissues in HF hinders progress in developing patient-specific strategies. Here, we provide a microscopy-based foundation for modeling conduction in HF tissues. We acquired 2D images of left ventricular tissues from HF patients (n = 16) and donors (n = 5). The composition and heterogeneity of fibrosis were quantified at a sub-micrometer resolution over an area of 1 mm2. From the images, we constructed computational bidomain models of tissue electrophysiology. We computed local upstroke velocities of the membrane voltage and anisotropic conduction velocities (CV). The non-myocyte volume fraction was higher in HF than donors (39.68 ± 14.23 vs. 22.09 ± 2.72%, p < 0.01), and higher in ischemic (IC) than nonischemic (NIC) cardiomyopathy (47.2 ± 16.18 vs. 32.16 ± 6.55%, p < 0.05). The heterogeneity of fibrosis within each subject was highest for IC (27.1 ± 6.03%) and lowest for donors (7.47 ± 1.37%) with NIC (15.69 ± 5.76%) in between. K-means clustering of this heterogeneity discriminated IC and NIC with an accuracy of 81.25%. The heterogeneity in CV increased from donor to NIC to IC tissues. CV decreased with increasing fibrosis for longitudinal (R 2 = 0.28, p < 0.05) and transverse conduction (R 2 = 0.46, p < 0.01). The tilt angle of the CV vectors increased 2.1° for longitudinal and 0.91° for transverse conduction per 1% increase in fibrosis. Our study suggests that conduction fundamentally differs in the two etiologies due to the characteristics of fibrosis. Our study highlights the importance of the etiology-specific modeling of HF tissues and integration of medical history into electrophysiology models for personalized risk stratification and treatment planning.

Dataset Information

A Computational Approach for Understanding the Interactions between Graphene Oxide and Nucleoside Diphosphate Kinase with Implications for Heart Failure.

Publications

A Computational Approach for Understanding the Interactions between Graphene Oxide and Nucleoside Diphosphate Kinase with Implications for Heart Failure.

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