Frontiers in Physiology, 15, 1489439:1-15 (2024)

IF 3,2

Nutraceuticals Silybin B, resveratrol, and epigallocatechin-3 gallate (EGCG) bind to cardiac muscle troponin to restore the loss of lusitropy caused by cardiomyopathy mutations in vitro, in vivo, and in silico

Yang Zeyu, Sheehan Alice M., Messer Andrew E., Tsui Sharmane, Sparrow Alexander, Redwood Charles, Křen Vladimír, Gould Ian R., Marston Steven B.

 Abstract

Adrenergic activation of protein kinase A (PKA) in cardiac muscle targets the sarcolemma, sarcoplasmic reticulum, and contractile apparatus to increase contractile force and heart rate. In the thin filaments of the contractile apparatus, cardiac troponin I (cTnI) Ser22 and Ser23 in the cardiacspecific N-terminal peptide (NcTnI: residues 1 to 32) are the targets for PKA phosphorylation. Phosphorylation causes a 2-3 fold decrease of affinity of cTn for Ca2+ associated with a higher rate of Ca2+ dissociation from cTnC leading to a faster relaxation rate of the cardiac muscle (lusitropy). Cardiomyopathy-linked mutations primarily affect Ca2+ regulation or the PAK-dependent modulatory system, such that Ca2+-sensitivity becomes independent of phosphorylation level (uncoupling) and this could be sufficient to induce cardiomyopathy. A drug that could restore the phosphorylation-dependent modulation of Ca2+-sensitivity could have potential for treatment of these pathologies. We have found that a number of small molecules, including silybin B, resveratrol and EGCG, can restore coupling in single filament assays.

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