TY - JOUR
T1 - Heart failure-related hyperphosphorylation in the cardiac troponin I C terminus has divergent effects on cardiac function in vivo
AU - Li, Yuejin
AU - Zhu, Guangshuo
AU - Paolocci, Nazareno
AU - Zhang, Pingbo
AU - Takahashi, Cyrus
AU - Okumus, Nazli
AU - Heravi, Amir
AU - Keceli, Gizem
AU - Ramirez-Correa, Genaro
AU - Kass, David A.
AU - Murphy, Anne M.
N1 - Publisher Copyright:
© 2017 American Heart Association, Inc.
PY - 2017/9/1
Y1 - 2017/9/1
N2 - BACKGROUND: In human heart failure, Ser199 (equivalent to Ser200 in mouse) of cTnI (cardiac troponin I) is significantly hyperphosphorylated, and in vitro studies suggest that it enhances myofilament calcium sensitivity and alters calpain-mediated cTnI proteolysis. However, how its hyperphosphorylation affects cardiac function in vivo remains unknown. METHODS AND RESULTS: To address the question, 2 transgenic mouse models were generated: a phospho-mimetic cTnIS200D and a phosphosilenced cTnIS200A, each driven by the cardiomyocyte-specific á-myosin heavy chain promoter. Cardiac structure assessed by echocardiography and histology was normal in both transgenic models compared with littermate controls (n=5). Baseline in vivo hemodynamics and isolated muscle studies showed that cTnIS200D significantly prolonged relaxation and lowered left ventricular peak filling rate, whereas ejection fraction and force development were normal (n=5). However, with increased heart rate or â-adrenergic stimulation, cTnIS200D mice had less enhanced ejection fraction or force development versus controls, whereas relaxation improved similarly to controls (n=5). By contrast, cTnIS200A was functionally normal both at baseline and under the physiological stresses. To test whether either mutation impacted cardiac response to ischemic stress, isolated hearts were subjected to ischemia/reperfusion. cTnIS200D were protected, recovering 88±8% of contractile function versus 35±15% in littermate controls and 28±8% in cTnIS200A (n=5). This was associated with less cTnI proteolysis in cTnIS200D hearts. CONCLUSIONS: Hyperphosphorylation of this serine in cTnI C terminus impacts heart function by depressing diastolic function at baseline and limiting systolic reserve under physiological stresses. However, paradoxically, it preserves heart function after ischemia/reperfusion injury, potentially by decreasing proteolysis of cTnI.
AB - BACKGROUND: In human heart failure, Ser199 (equivalent to Ser200 in mouse) of cTnI (cardiac troponin I) is significantly hyperphosphorylated, and in vitro studies suggest that it enhances myofilament calcium sensitivity and alters calpain-mediated cTnI proteolysis. However, how its hyperphosphorylation affects cardiac function in vivo remains unknown. METHODS AND RESULTS: To address the question, 2 transgenic mouse models were generated: a phospho-mimetic cTnIS200D and a phosphosilenced cTnIS200A, each driven by the cardiomyocyte-specific á-myosin heavy chain promoter. Cardiac structure assessed by echocardiography and histology was normal in both transgenic models compared with littermate controls (n=5). Baseline in vivo hemodynamics and isolated muscle studies showed that cTnIS200D significantly prolonged relaxation and lowered left ventricular peak filling rate, whereas ejection fraction and force development were normal (n=5). However, with increased heart rate or â-adrenergic stimulation, cTnIS200D mice had less enhanced ejection fraction or force development versus controls, whereas relaxation improved similarly to controls (n=5). By contrast, cTnIS200A was functionally normal both at baseline and under the physiological stresses. To test whether either mutation impacted cardiac response to ischemic stress, isolated hearts were subjected to ischemia/reperfusion. cTnIS200D were protected, recovering 88±8% of contractile function versus 35±15% in littermate controls and 28±8% in cTnIS200A (n=5). This was associated with less cTnI proteolysis in cTnIS200D hearts. CONCLUSIONS: Hyperphosphorylation of this serine in cTnI C terminus impacts heart function by depressing diastolic function at baseline and limiting systolic reserve under physiological stresses. However, paradoxically, it preserves heart function after ischemia/reperfusion injury, potentially by decreasing proteolysis of cTnI.
KW - Calpain
KW - Phosphorylation
KW - Proteolysis
KW - Serine
KW - Troponin I
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U2 - 10.1161/CIRCHEARTFAILURE.117.003850
DO - 10.1161/CIRCHEARTFAILURE.117.003850
M3 - Article
C2 - 28899987
AN - SCOPUS:85030435733
SN - 1941-3289
VL - 10
JO - Circulation: Heart Failure
JF - Circulation: Heart Failure
IS - 9
M1 - e003850
ER -