Abstract:Aims: The transient receptor potential canonical channel 1 (TRPC1) is a crucial component of the stretch-activated ion channels (SACs). The objective of this research was to demonstrate the contribution of TRPC1 in maintaining cardiac contractile function in the hypertrophic myocardium. Methods: Hypertrophic rat hearts were induced by injecting isoproterenol intraperitoneally, and the expressions of TRPC1/3/6 and Na+/Ca2+ exchanger 1 (NCX1) proteins were analyzed by Western blot. The intr… Show more
“…Our simulations indicate that in physiological conditions the cardiac muscle cells work in the low-medium [Ca 2+ ] region of the force-[Ca 2+ ] relationship. Therefore, at higher preloads, while the shifting of ECa 50 at longer SLs observed at the single fiber level exerts a role in the whole organ behavior, the higher T max has a limited or absent effect.Figure 8Simulated ejection volume at different preloads (grey circles) and comparison with experimental data 40 for rat myocardium (filled dots) and old model (grey boxes). The new model is able to predict an increase in the ejection volume at higher preloads, due to the higher tension generated at longer SLs.…”
The molecular bases of the Frank-Starling law of the heart and of its cellular counterpart, the length dependent activation (LDA), are largely unknown. However, the recent discovery of the thick filament activation, a second pathway beside the well-known calcium mediated thin filament activation, is promising for elucidating these mechanisms. The thick filament activation is mediated by the tension acting on it through the mechano-sensing (MS) mechanism and can be related to the LDA via the titin passive tension. Here, we propose a mechanism to explain the higher maximum tension at longer sarcomere lengths generated by a maximally activated muscle and test it in-silico with a single fiber and a ventricle model. The active tension distribution along the thick filament generates a reservoir of inactive motors at its free-end that can be activated by passive tension on a beat-to-beat timescale. The proposed mechanism is able to quantitatively account for the observed increment in tension at the fiber level, however, the ventricle model suggests that this component of the LDA is not crucial in physiological conditions.
“…Our simulations indicate that in physiological conditions the cardiac muscle cells work in the low-medium [Ca 2+ ] region of the force-[Ca 2+ ] relationship. Therefore, at higher preloads, while the shifting of ECa 50 at longer SLs observed at the single fiber level exerts a role in the whole organ behavior, the higher T max has a limited or absent effect.Figure 8Simulated ejection volume at different preloads (grey circles) and comparison with experimental data 40 for rat myocardium (filled dots) and old model (grey boxes). The new model is able to predict an increase in the ejection volume at higher preloads, due to the higher tension generated at longer SLs.…”
The molecular bases of the Frank-Starling law of the heart and of its cellular counterpart, the length dependent activation (LDA), are largely unknown. However, the recent discovery of the thick filament activation, a second pathway beside the well-known calcium mediated thin filament activation, is promising for elucidating these mechanisms. The thick filament activation is mediated by the tension acting on it through the mechano-sensing (MS) mechanism and can be related to the LDA via the titin passive tension. Here, we propose a mechanism to explain the higher maximum tension at longer sarcomere lengths generated by a maximally activated muscle and test it in-silico with a single fiber and a ventricle model. The active tension distribution along the thick filament generates a reservoir of inactive motors at its free-end that can be activated by passive tension on a beat-to-beat timescale. The proposed mechanism is able to quantitatively account for the observed increment in tension at the fiber level, however, the ventricle model suggests that this component of the LDA is not crucial in physiological conditions.
“…In both cases, the predicted ejection is constant when the preload leads to a completely overlapping geometry of the sarcomeres. Simulations were also compared with experimental data 22 (black diamonds), showing a good fit at low preloads. The discrepancies in fit at higher preloads probably were attributable to involvement of other regulatory systems, like thin-filament regulation and lattice-spacing effects, not included in our model.…”
Recent experimental evidence in skeletal muscle demonstrated the existence of a thick-filament mechanosensing mechanism, acting as a second regulatory system for muscle contraction, in addition to calcium-mediated thin filament regulation. These two systems cooperate to generate force, but the extent to which their interaction is relevant in physiologically contracting muscle was not yet assessed experimentally. Therefore, we included both regulatory mechanisms in a mathematical model of rat trabecula and whole ventricle. No additional regulatory mechanisms were considered in our model. Our simulations suggested that mechanosensing regulation is not limited to the initial phases of contraction but, instead, is crucial during physiological contraction. An important consequence of this finding is that titin mediated thick filament activation can account for several sarcomere length dependencies observed in contracting muscle. Under the hypothesis that a similar mechanism is acting on cardiac muscle, and within the limits of a finite element left ventricle model, we predict that these two regulatory mechanisms are crucial for the molecular basis of the Frank-Starling law of the heart.
“…Prolonged pressure overload induces heart hypertrophy, which advances to heart failure. In addition to the blood pressure stimulation on cardiomyocytes, abnormal intracellular Ca 2+ homeostasis in the myocardium has been suggested to be a cause of cardiac hypertrophy [23,24]. An elevated [Ca 2+ ] i activates several Ca 2+ -dependent signaling pathways, which eventually results in cardiac hypertrophy [25][26][27].…”
Background/Aims: Intracellular calcium concentration ([Ca2+]i) homeostasis, an initial factor of cardiac hypertrophy, is regulated by the calcium-sensing receptor (CaSR) and is associated with the formation of autolysosomes. The aim of this study was to investigate the role of Calhex231, a CaSR inhibitor, on the hypertrophic response via autophagy modulation. Methods: Cardiac hypertrophy was induced by transverse aortic constriction (TAC) in 40 male Wistar rats, while 10 rats underwent a sham operation and served as controls. Cardiac function was monitored by transthoracic echocardiography, and the hypertrophy index was calculated. Cardiac tissue was stained with hematoxylin and eosin (H&E) or Masson's trichrome reagent and examined by transmission electron microscopy. An angiotensin II (Ang II)-induced cardiomyocyte hypertrophy model was established and used to test the involvement of active molecules. Intracellular calcium concentration ([Ca2+]i) was determined by the introduction of Fluo-4/AM dye followed by confocal microscopy. The expression of various active proteins was analyzed by western blot. Results: The rats with TAC-induced hypertrophy had an increased heart size, ratio of heart weight to body weight, myocardial fibrosis, and CaSR and autophagy levels, which were suppressed by Calhex231. Experimental results using Ang II-induced hypertrophic cardiomyocytes confirmed that Calhex231 suppressed CaSR expression and downregulated autophagy by inhibiting the Ca2+/calmodulin-dependent-protein kinase-kinase-β (CaMKKβ)- AMP-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR) pathway to ameliorate cardiomyocyte hypertrophy. Conclusions: Calhex231 ameliorates myocardial hypertrophy induced by pressure-overload or Ang II via inhibiting CaSR expression and autophagy. Our results may support the notion that Calhex231 can become a new therapeutic agent for the treatment of cardiac hypertrophy.
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