In transgenic mice, the phospho-mimetic cTnIS200D mutation preserved heart function after ischemia/reperfusion injury, recovering 88±8% of contractile function versus 35±15% in controls.
Does hyperphosphorylation of cTnI Ser200 alter cardiac function and response to ischemia/reperfusion in transgenic mouse models?
Hyperphosphorylation of cTnI Ser200 depresses baseline diastolic function and limits systolic reserve, but paradoxically preserves heart function after ischemia/reperfusion injury.
Absolute Event Rate: 88% vs 35%
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 phospho-silenced cTnIS200A, each driven by the cardiomyocyte-specific α-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 β-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.
Li et al. (2017) studied Heart failure. Phospho-mimetic cTnIS200D mutation vs. Littermate controls and cTnIS200A was evaluated on Recovery of contractile function after ischemia/reperfusion. In transgenic mice, the phospho-mimetic cTnIS200D mutation preserved heart function after ischemia/reperfusion injury, recovering 88±8% of contractile function versus 35±15% in controls.