TY  - JOUR
A1  - Budde, Heidi
A1  - Hassoun, Roua
A1  - Tangos, Melina
A1  - Zhazykbayeva, Saltanat
A1  - Herwig, Melissa
A1  - Varatnitskaya, Marharyta
A1  - Sieme, Marcel
A1  - Delalat, Simin
A1  - Sultana, Innas
A1  - Kolijn, Detmar
A1  - Gömöri, Kamilla
A1  - Jarkas, Muhammad
A1  - Lódi, Mária
A1  - Jaquet, Kornelia
A1  - Kovács, Árpád
A1  - Mannherz, Hans Georg
A1  - Sequeira, Vasco
A1  - Mügge, Andreas
A1  - Leichert, Lars I.
A1  - Sossalla, Samuel
A1  - Hamdani, Nazha
T1  - The interplay between S-glutathionylation and phosphorylation of cardiac troponin I and myosin binding protein C in end-stage human failing hearts
JF  - Antioxidants
N2  - Oxidative stress is defined as an imbalance between the antioxidant defense system and the production of reactive oxygen species (ROS). At low levels, ROS are involved in the regulation of redox signaling for cell protection. However, upon chronical increase in oxidative stress, cell damage occurs, due to protein, DNA and lipid oxidation. Here, we investigated the oxidative modifications of myofilament proteins, and their role in modulating cardiomyocyte function in end-stage human failing hearts. We found altered maximum Ca\(^{2+}\)-activated tension and Ca\(^{2+}\) sensitivity of force production of skinned single cardiomyocytes in end-stage human failing hearts compared to non-failing hearts, which was corrected upon treatment with reduced glutathione enzyme. This was accompanied by the increased oxidation of troponin I and myosin binding protein C, and decreased levels of protein kinases A (PKA)- and C (PKC)-mediated phosphorylation of both proteins. The Ca\(^{2+}\) sensitivity and maximal tension correlated strongly with the myofilament oxidation levels, hypo-phosphorylation, and oxidative stress parameters that were measured in all the samples. Furthermore, we detected elevated titin-based myocardial stiffness in HF myocytes, which was reversed by PKA and reduced glutathione enzyme treatment. Finally, many oxidative stress and inflammation parameters were significantly elevated in failing hearts compared to non-failing hearts, and corrected upon treatment with the anti-oxidant GSH enzyme. Here, we provide evidence that the altered mechanical properties of failing human cardiomyocytes are partially due to phosphorylation, S-glutathionylation, and the interplay between the two post-translational modifications, which contribute to the development of heart failure.
KW  - myofilament proteins
KW  - oxidative stress
KW  - inflammation
KW  - phosphorylation
KW  - S-glutathionylation
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-242701
SN  - 2076-3921
VL  - 10
IS  - 7
ER  - 
TY  - JOUR
A1  - Sequeira, Vasco
T1  - When fat meets the engine: implications of dietary rumenic acid on myosin-targeting therapies in heart failure
JF  - Journal of Physiology
N2  - No abstract available.
KW  - rumenic acid
KW  - cardiomyopathy
KW  - mavacamten
KW  - myosin
KW  - omecamtiv mecarbil
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-259693
VL  - 599
IS  - 15
ER  - 
TY  - JOUR
A1  - Sacchetto, Claudia
A1  - Sequeira, Vasco
A1  - Bertero, Edoardo
A1  - Dudek, Jan
A1  - Maack, Christoph
A1  - Calore, Martina
T1  - Metabolic Alterations in Inherited Cardiomyopathies
JF  - Journal of Clinical Medicine
N2  - The normal function of the heart relies on a series of complex metabolic processes orchestrating the proper generation and use of energy. In this context, mitochondria serve a crucial role as a platform for energy transduction by supplying ATP to the varying demand of cardiomyocytes, involving an intricate network of pathways regulating the metabolic flux of substrates. The failure of these processes results in structural and functional deficiencies of the cardiac muscle, including inherited cardiomyopathies. These genetic diseases are characterized by cardiac structural and functional anomalies in the absence of abnormal conditions that can explain the observed myocardial abnormality, and are frequently associated with heart failure. Since their original description, major advances have been achieved in the genetic and phenotype knowledge, highlighting the involvement of metabolic abnormalities in their pathogenesis. This review provides a brief overview of the role of mitochondria in the energy metabolism in the heart and focuses on metabolic abnormalities, mitochondrial dysfunction, and storage diseases associated with inherited cardiomyopathies.
KW  - inherited cardiomyopathies
KW  - mitochondria
KW  - cardiac metabolism
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-193806
SN  - 2077-0383
VL  - 8
IS  - 12
ER  -