Objetivos tempranos y deterioro progresivo del rendimiento cardíaco en respuesta a la troponina I cardíaca modificada crónicamente

Protein kinase C (PKC) targeted thin filament cardiac troponin I (cTnI) Ser43/45 phosphorylation (p-S43/45) increases during heart failure (HF). Chronic cTnI p-S43/45 causes contractile dysfunction in cardiac myocytes, but the in vivo impact is less clear. To investigate the in vivo impact of this cluster, three lines of transgenic mice were generated with high (HE-), moderate (ME-), and low (LE-) phospho-mimetic cTnIS43/45D (SD) replacement of endogenous cTnI within sarcomere thin filament. Each mouse line developed chronic in vivo and/or cellular contractile dysfunction, which initiated structural remodeling and a progressive deterioration in cardiac function. Higher cTnISD replacement levels accelerated the rate of deterioration and progression to end-stage heart failure. In further work, cTnISD initiated sarcomere communication to produce early alterations in mitochondria prior to the progressive deterioration in cardiac performance. Specifically, early reductions developed in mitochondrial/nuclear DNA, mitochondrial master regulator gene expression, electron transport proteins, and anti-oxidants along with increased mitochondrial-related oxidative stress prior to extensive remodeling in cTnISD mice. In addition, cTnISD mice developed early differences in mitochondrial ultrastructure and evidence favoring fusion over fission compared to non-transgenic (ntg) littermates. A second generation peptide derived from elamipretide improved survival and slowed the progression of remodeling and contractile dysfunction. Overall, the results demonstrate chronic cTnISD causes cardiac dysfunction and initiates early mitochondrial responses that serve as an important driver of a progressive deterioration in cardiac performance to end-stage HF.