Abstract
The NH2-terminal variable region of cardiac troponin T (cTnT) is restrictively removed in myocardial ischemia-reperfusion. Over-expression of the NH2-terminal truncated cTnT (cTnT-ND) showed a compensatory effect on cardiac function in transgenic mice. Here we further investigated the production of cTnT-ND following in vivo ischemia-reperfusion. Ischemia of 45 min and reperfusion of 3 or 2 hours was produced in vivo in adult pig and mouse hearts. In both models, viable versus necrotic myocardium was delineated by tetrazolium staining. Four isoforms of cTnT were found in the adult pig cardiac muscle. cDNA cloning and sequencing revealed their difference in the NH2-terminal variable region. An increase of fragmented cTnT was found in the salvaged and viable, previously ischemic region of the infarcted pig hearts as detected using a monoclonal antibody (mAb) recognizing the middle region of cTnT. The four cTnT isoforms with NH2-terminal variations produced cTnT fragments of identical size. A mAb raised against the NH2-terminal peptide of cTnT recognized intact but not the fragmented pig cTnT, indicating an NH2-terminal truncation. Myocardial ischemia-reperfusion in conscious mice produced abnormal EKG and reduced ventricular contractile function, accompanied by high levels of cTnT-ND in viable, previously ischemic myocardium. The results demonstrated that the production of cTnT-ND in salvaged cardiac muscle by posttranslational modification is an active and potentially adaptive response to ischemia/reperfusion rather than a consequence of cardiomyocyte death. This concept is supported by enhanced recovery of cardiac function from ischemia-reperfusion in transgenic mice with cardiac over-expression of cTnT-ND versus wild-type controls. These results suggest that the restrictive NH2-terminal truncation of cTnT is a novel posttranslational mechanism that preserves ventricular function in response to myocardial energetic crisis and provides a potential therapeutic target.
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