VEGA 2/0182/21

Principal Investigator: Alexandra Zahradníková jr.

Duration: January 2021 – December 2024
Coordinating Organization: Institute of Experimental Endocrinology BRC SAS

Annotation:

Heart failure is a prominent cause of death in contemporary society. The development of heart failure is accompanied by marked changes in the energetics of the myocardium. Therapy by a cocktail of B vitamins, targeted at mitochondrial energetics, showed a promising cardioprotective effect on the development and progression of heart failure. However, it is not known to what extent does the protection result from remodelling of the calcium signalling systems. Our aim is to identify the relationship between the structural dynamics of dyads, the quality of excitation-contraction coupling, and the changes of junctophilin expression in a model of cardiac pressure overload in mouse. In line with the translational potential of metabolic therapy, we will also evaluate its effect in the context of standard heart failure medication (ß-blockers, ACE inhibitors). The results will foster the understanding of maladaptive processes of cardiac hypertrophy during emergence, development and therapy of heart failure at the cellular and molecular level.

Keywords:

heart failure, cardiac myocyte, dyad, calcium signalling, remodeling

Objectives:

The aim of the project is to identify mechanisms of restoration of cardiac function during the heart failure (HF) therapy, focused on remodeling of the dyadic system of cardiomyocytes. We will search for the relation between the degree of myocardial functional impairment, the quality of excitation-contraction coupling in cardiac myocytes, and the structure of dyads in the context of metabolic and standard heart failure therapy.

Aim 1: To identify the effect of metabolic or standard therapy of heart failure on:

• expression and stability of the dyadic structural protein JP-2 in ventricular cardiac myocytes,
• remodeling of the dyadic system of ventricular cardiac myocytes,
• quality of excitation-contraction coupling, calcium signaling and contractility of ventricular cardiac myocytes.

Aim 2: To reveal the causal relationship between the changes of myocardial function, the amount and integrity of JP-2, the degree of dyadic system remodeling, and the quality of excitation-contraction coupling of isolated myocytes during the development and therapy of heart failure.

Publications: