Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:2.3.3.1 (
citrate synthase
)
4,488
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Hypothyroidism (Hypo) is a risk factor for cardiovascular diseases, including heart failure. Hypo rapidly induces Ca
2+
mishandling and contractile dysfunction (CD), as well as atrophy and ventricular myocytes (VM) remodeling. Hypo decreases SERCA-to-phospholamban ratio (SERCA/
PLB
), and thereby contributes to CD. Nevertheless, detailed spatial and temporal Ca
2+
cycling characterization in VM is missing, and contribution of other structural and functional changes to the mechanism underlying Ca
2+
mishandling and CD, as transverse tubules (T-T) remodeling, mitochondrial density (D
mit
) and energy availability, is unclear. Therefore, in a rat model of Hypo, we aimed to characterize systolic and diastolic Ca
2+
signaling, T-T remodeling, D
mit
,
citrate synthase
(CS) activity and high-energy phosphate metabolites (ATP and phosphocreatine). We confirmed a decrease in SERCA/
PLB
(59%), which slowed SERCA activity (48%), reduced SR Ca
2+
(19%) and blunted Ca
2+
transient amplitude (41%). Moreover, assessing the rate of SR Ca
2+
release (dRel/dt), we found that early and maximum dRel/dt decreased, and this correlated with staggered Ca
2+
transients. However, dRel/dt persisted during Ca
2+
transient relaxation due to abundant late Ca
2+
sparks. Isoproterenol significantly up-regulated systolic Ca
2+
cycling. T-T were unchanged, hence, cannot explain staggered Ca
2+
transients and altered dRel/dt. Therefore, we suggest that these might be caused by RyR2 clusters desynchronization, due to diminished Ca
2+
-dependent sensitivity of RyR2, which also caused a decrease in diastolic SR Ca
2+
leak. Furthermore, D
mit
was unchanged and CS activity slightly decreased (14%), however, the ratio phosphocreatine/ATP did not change, therefore, energy deficiency cannot account for Ca
2+
and contractility dysregulation. We conclude that decreased SR Ca
2+
, due to slower SERCA, disrupts systolic RyR2 synchronization, and this underlies CD.
...
PMID:Underlying mechanism of the contractile dysfunction in atrophied ventricular myocytes from a murine model of hypothyroidism. 2974 31
