TY - GEN
T1 - Mechanosensitive Channel Piezo1 in R403Q Hypertrophic Cardiomyopathy: A Computational Study
AU - Forouzandehmehr, M.
AU - Ghosi, S.
AU - Paci, M.
AU - Hyttinen, J.
AU - Koivumäki, J.
PY - 2023
Y1 - 2023
N2 - Piezo1 is a tension-gated cation channel with a voltage-dependent inactivation and Ca2+-permeability. In mice, cardiac Piezo1 shows maladaptive dynamics and evokes a hypertrophic response to pressure overload. Mutation-specific hypertrophic feedback to Piezo1 has not been addressed before. Here, we present a novel mechanistic model of Piezo1 current and add it to our in silico whole-cell model of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) to study the mechanotransduction in the presence of MYH7R403Q/+ condition. Our biophysical model of Piezo1 has a tension-dependent activation and a novel voltage-dependent inactivation gate. We modeled MYH7R403Q/+ hypertrophic cardiomyopathy (HCM) following our previous model by altering DRX/SRX myosin ratio and elevating myofilament MgADP and inorganic phosphate. Normalized current-tension relationships of Piezo1 showed a 27.9% increase in Boltzmann slope due to MYH7R403Q/+ HCM. However, the half-maximal activation (P50) elevated 16.7%. This work contributes to investigations on the capacity of mechanotransduction, particularly cardiac Piezo1 channel, as a potential drug target for mutation-specific HCM.
AB - Piezo1 is a tension-gated cation channel with a voltage-dependent inactivation and Ca2+-permeability. In mice, cardiac Piezo1 shows maladaptive dynamics and evokes a hypertrophic response to pressure overload. Mutation-specific hypertrophic feedback to Piezo1 has not been addressed before. Here, we present a novel mechanistic model of Piezo1 current and add it to our in silico whole-cell model of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) to study the mechanotransduction in the presence of MYH7R403Q/+ condition. Our biophysical model of Piezo1 has a tension-dependent activation and a novel voltage-dependent inactivation gate. We modeled MYH7R403Q/+ hypertrophic cardiomyopathy (HCM) following our previous model by altering DRX/SRX myosin ratio and elevating myofilament MgADP and inorganic phosphate. Normalized current-tension relationships of Piezo1 showed a 27.9% increase in Boltzmann slope due to MYH7R403Q/+ HCM. However, the half-maximal activation (P50) elevated 16.7%. This work contributes to investigations on the capacity of mechanotransduction, particularly cardiac Piezo1 channel, as a potential drug target for mutation-specific HCM.
U2 - 10.22489/CinC.2023.359
DO - 10.22489/CinC.2023.359
M3 - Conference contribution
T3 - Computing in cardiology
SP - 1
EP - 4
BT - 2023 Computing in Cardiology (CinC)
PB - IEEE
T2 - Computing in Cardiology
Y2 - 1 October 2023 through 4 October 2023
ER -