Cargando…

Increase in PKCα Activity during Heart Failure Despite the Stimulation of PKCα Braking Mechanism

Rationale: Heart failure (HF) is marked by dampened cardiac contractility. A mild therapeutic target that improves contractile function without desensitizing the β-adrenergic system during HF may improve cardiac contractility and potentially survival. Inhibiting protein kinase C α (PKCα) activity ma...

Descripción completa

Detalles Bibliográficos
Autor principal: Aslam, Naveed
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7177253/
https://www.ncbi.nlm.nih.gov/pubmed/32272716
http://dx.doi.org/10.3390/ijms21072561
_version_ 1783525177602080768
author Aslam, Naveed
author_facet Aslam, Naveed
author_sort Aslam, Naveed
collection PubMed
description Rationale: Heart failure (HF) is marked by dampened cardiac contractility. A mild therapeutic target that improves contractile function without desensitizing the β-adrenergic system during HF may improve cardiac contractility and potentially survival. Inhibiting protein kinase C α (PKCα) activity may fit the criteria of a therapeutic target with milder systemic effects that still boosts contractility in HF patients. PKCα activity has been observed to increase during HF. This increase in PKCα activity is perplexing because it is also accompanied by up-regulation of a molecular braking mechanism. Objective: I aim to explore how PKCα activity can be increased and maintained during HF despite the presence of a molecular braking mechanism. Methods and Results: Using a computational approach, I show that the local diacylglycerol (DAG) signaling is regulated through a two-compartment signaling system in cardiomyocytes. These results imply that after massive myocardial infarction (MI), local homeostasis of DAG signaling is disrupted. The loss of this balance leads to prolonged activation of PKCα, a key molecular target linked to LV remodeling and dysfunctional filling and ejection in the mammalian heart. This study also proposes an explanation for how DAG homeostasis is regulated during normal systolic and diastolic cardiac function. Conclusions: I developed a novel two-compartment computational model for regulating DAG homeostasis during Ang II-induced heart failure. This model provides a promising tool with which to study mechanisms of DAG signaling regulation during heart failure. The model can also aid in identification of novel therapeutic targets with the aim of improving the quality of life for heart failure patients.
format Online
Article
Text
id pubmed-7177253
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-71772532020-04-28 Increase in PKCα Activity during Heart Failure Despite the Stimulation of PKCα Braking Mechanism Aslam, Naveed Int J Mol Sci Article Rationale: Heart failure (HF) is marked by dampened cardiac contractility. A mild therapeutic target that improves contractile function without desensitizing the β-adrenergic system during HF may improve cardiac contractility and potentially survival. Inhibiting protein kinase C α (PKCα) activity may fit the criteria of a therapeutic target with milder systemic effects that still boosts contractility in HF patients. PKCα activity has been observed to increase during HF. This increase in PKCα activity is perplexing because it is also accompanied by up-regulation of a molecular braking mechanism. Objective: I aim to explore how PKCα activity can be increased and maintained during HF despite the presence of a molecular braking mechanism. Methods and Results: Using a computational approach, I show that the local diacylglycerol (DAG) signaling is regulated through a two-compartment signaling system in cardiomyocytes. These results imply that after massive myocardial infarction (MI), local homeostasis of DAG signaling is disrupted. The loss of this balance leads to prolonged activation of PKCα, a key molecular target linked to LV remodeling and dysfunctional filling and ejection in the mammalian heart. This study also proposes an explanation for how DAG homeostasis is regulated during normal systolic and diastolic cardiac function. Conclusions: I developed a novel two-compartment computational model for regulating DAG homeostasis during Ang II-induced heart failure. This model provides a promising tool with which to study mechanisms of DAG signaling regulation during heart failure. The model can also aid in identification of novel therapeutic targets with the aim of improving the quality of life for heart failure patients. MDPI 2020-04-07 /pmc/articles/PMC7177253/ /pubmed/32272716 http://dx.doi.org/10.3390/ijms21072561 Text en © 2020 by the author. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Aslam, Naveed
Increase in PKCα Activity during Heart Failure Despite the Stimulation of PKCα Braking Mechanism
title Increase in PKCα Activity during Heart Failure Despite the Stimulation of PKCα Braking Mechanism
title_full Increase in PKCα Activity during Heart Failure Despite the Stimulation of PKCα Braking Mechanism
title_fullStr Increase in PKCα Activity during Heart Failure Despite the Stimulation of PKCα Braking Mechanism
title_full_unstemmed Increase in PKCα Activity during Heart Failure Despite the Stimulation of PKCα Braking Mechanism
title_short Increase in PKCα Activity during Heart Failure Despite the Stimulation of PKCα Braking Mechanism
title_sort increase in pkcα activity during heart failure despite the stimulation of pkcα braking mechanism
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7177253/
https://www.ncbi.nlm.nih.gov/pubmed/32272716
http://dx.doi.org/10.3390/ijms21072561
work_keys_str_mv AT aslamnaveed increaseinpkcaactivityduringheartfailuredespitethestimulationofpkcabrakingmechanism