Oxidative Stress and Respiratory Muscle Weakness in Heart Failure with Reduced Ejection Fraction

Project: Research

Investigators

  • Ravi Armand Kumar (PI)

Description

Heart failure with reduced ejection fraction (HFrEF) causes inspiratory dysfunction that directly contributes to the defining disease symptoms of dyspnea, impaired airway clearance, and exercise intolerance. This inspiratory dysfunction stems from weakness in the diaphragm muscle and persists despite optimal cardiac-centered medical treatment or heart transplant. Diaphragm weakness is caused by rampant oxidative stress that can damage myofibrillar and mitochondrial proteins, but the sources of increased free radicals in HFrEF are poorly understood. This project will investigate two potential sources - NAD(P)H Oxidase 2 (Nox2) and the mitochondria. The central hypothesis of my proposal is that overexpression of Nox2 and increased mitochondrial reactive oxygen species are the root cause of diaphragm weakness in HFrEF. We will test this hypothesis in a murine model by 1) overexpressing subunits of the Nox2 complex in the diaphragm muscle to see if they are sufficient to induce weakness as seen in HFrEF; and 2) administering an antioxidant enzyme, catalase, specifically targeted to the diaphragm mitochondria as a therapeutic intervention for HFrEF. We will induce genetic modifications (Nox2 subunits and mitochondrial antioxidant) through viral delivery of packaged plasmids driven by a skeletal muscle-specific promoter and induce HFrEF via myocardial infarction. We will measure exercise capacity, diaphragm muscle weakness, and mitochondrial function to examine how our interventions affect critical symptoms of severe HFrEF. The projects proposed within will provide potential targets to prevent HFrEF-associated diaphragm weakness and related symptoms as well as advance our understanding of redox homeostasis in skeletal muscle.
Award amount$62,032.00
Award date01/01/2020
Program typePredoctoral Fellowship
Award ID20PRE35200047
Effective start/end date01/01/202012/31/2021
StatusActive