Abstract
Background and Objectives: Tissue remodelling as a result of chronic hypertension or following myocardial infarction (MI) results in cardiac hypertrophy and ultimately heart failure. Elucidating signalling mechanisms that promote tissue injury/repair in these processes is paramount to developing safer and more effective treatment strategies. Recent evidence indicates Transglutaminase 2 (TG2) and its transamidase activity play a central role in tissue injury/repair. We analysed the role of TG2 in cardiac remodelling in response to two cardiac stressors: 1) transverse aortic constriction (TAC) to induce chronic pressure overload (a model of hypertension and aortic stenosis) and 2) MI injury. Study Design: Cardiac hypertrophy was induced by TAC-banding wild-type, TG2 knockout and mutant TG2 knock-in mice in which the wild-type Tgm2 gene was replaced by a single amino acid change that disinhibits TG2 enzyme activity. MI was induced by ligation of the left anterior descending (LAD) artery of wild-type and TG2 knockout mice. Results: We observed no difference between genotypes with respect to development of left ventricular hypertrophy, echocardiographic or hemodynamic parameters in TAC-banded mice. We did, however, observe a striking increase in incidence of post-infarct ventricular free wall rupture in TG2 KO vs wild-type mice in both males (100% vs 70.6%, p < 0.044) and females (72.2% vs 28.6%, p < 0.017), respectively. We are currently characterising the molecular mechanisms by which TG2 modulates tissue injury/repair following MI. Conclusions: Characterisation of the role of TG2 in modulating tissue injury/repair following MI should provide major mechanistic insights and may have significant implications for future treatment strategies post-infarct.
Published Version
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