TY - JOUR
T1 - Cardiac troponin i Pro82Ser variant induces diastolic dysfunction, blunts β-adrenergic response, and impairs myofilament cooperativity
AU - Ramirez-Correa, Genaro A.
AU - Frazier, Aisha H.
AU - Zhu, Guangshuo
AU - Zhang, Pingbo
AU - Rappold, Thomas
AU - Kooij, Viola
AU - Bedja, Djahida
AU - Snyder, Greg A.
AU - Lugo-Fagundo, Nahyr S.
AU - Hariharan, Raena
AU - Li, Yuejin
AU - Shen, Xiaoxu
AU - Gao, Wei Dong
AU - Cingolani, Oscar H.
AU - Takimoto, Eiki
AU - Foster, D. Brian
AU - Murphy, Anne M.
PY - 2015/1/15
Y1 - 2015/1/15
N2 - Troponin I (TnI) variant Pro82Ser (cTnIP82S) was initially considered a disease-causing mutation; however, later studies suggested the contrary. We tested the hypothesis of whether a causal link exists between cTnIP82S and cardiac structural and functional remodeling, such as during aging or chronic pressure overload. A cardiac-specific transgenic (Tg) mouse model of cTnIP82S was created to test this hypothesis. During aging, Tg cTnIP82S displayed diastolic dysfunction, characterized by longer isovolumetric relaxation time, and impaired ejection and relaxation time. In young, Tg mice in vivo pressurevolume loops and intact trabecular preparations revealed normal cardiac contractility at baseline. However, upon β-adrenergic stimulation, a blunted contractile reserve and no hastening in left ventricle relaxation were evident in vivo, whereas, in isolated muscles, Ca2+ transient amplitude isoproterenol dose-response was blunted. In addition, when exposed to chronic pressure overload, Tg mice show exacerbated hypertrophy and decreased contractility compared with age-matched non-Tg littermates. At the molecular level, this mutation significantly impairs myofilament cooperative activation. Importantly, this occurs in the absence of alterations in TnI or myosin-binding protein C phosphorylation. The cTnIP82S variant occurs near a region of interactions with troponin T; therefore, structural changes in this region could explain its meaningful effects on myofilament cooperativity. Our data indicate that cTnIP82S mutation modifies age-dependent diastolic dysfunction and impairs overall contractility after β-adrenergic stimulation or chronic pressure overload. Thus cTnIP82S variant should be regarded as a disease-modifying factor for dysfunction and adverse remodeling with aging and chronic pressure overload.
AB - Troponin I (TnI) variant Pro82Ser (cTnIP82S) was initially considered a disease-causing mutation; however, later studies suggested the contrary. We tested the hypothesis of whether a causal link exists between cTnIP82S and cardiac structural and functional remodeling, such as during aging or chronic pressure overload. A cardiac-specific transgenic (Tg) mouse model of cTnIP82S was created to test this hypothesis. During aging, Tg cTnIP82S displayed diastolic dysfunction, characterized by longer isovolumetric relaxation time, and impaired ejection and relaxation time. In young, Tg mice in vivo pressurevolume loops and intact trabecular preparations revealed normal cardiac contractility at baseline. However, upon β-adrenergic stimulation, a blunted contractile reserve and no hastening in left ventricle relaxation were evident in vivo, whereas, in isolated muscles, Ca2+ transient amplitude isoproterenol dose-response was blunted. In addition, when exposed to chronic pressure overload, Tg mice show exacerbated hypertrophy and decreased contractility compared with age-matched non-Tg littermates. At the molecular level, this mutation significantly impairs myofilament cooperative activation. Importantly, this occurs in the absence of alterations in TnI or myosin-binding protein C phosphorylation. The cTnIP82S variant occurs near a region of interactions with troponin T; therefore, structural changes in this region could explain its meaningful effects on myofilament cooperativity. Our data indicate that cTnIP82S mutation modifies age-dependent diastolic dysfunction and impairs overall contractility after β-adrenergic stimulation or chronic pressure overload. Thus cTnIP82S variant should be regarded as a disease-modifying factor for dysfunction and adverse remodeling with aging and chronic pressure overload.
KW - Cardiac troponin I mutation
KW - Diastolic dysfunction
KW - Hypertrophy
KW - Transgenic mouse
UR - http://www.scopus.com/inward/record.url?scp=84921349210&partnerID=8YFLogxK
U2 - 10.1152/japplphysiol.00463.2014
DO - 10.1152/japplphysiol.00463.2014
M3 - Article
C2 - 25324519
AN - SCOPUS:84921349210
SN - 8750-7587
VL - 118
SP - 212
EP - 223
JO - Journal of Applied Physiology
JF - Journal of Applied Physiology
IS - 2
ER -