With increasing prevalence and incidence rates over time, heart failure is well-recognised as a chronic disease with lifelong management, and is one of the top killers in the modern world, accounting for around 40 percent of deaths. Cardiac hypertrophy is defined as a compensatory mechanism induced by augmented mechanical and neurohumoral stress stimulation to preserve cardiac function. Nevertheless, sustained cardiac hypertrophy can lead to cardiac dysfunction. Prolonged activation of Angiotensin II is one of the main mediators that contributes to the development and maintenance of cardiac hypertrophy via its hemodynamic and cardiotrophic effects, and metabolizing Angiotensin II into favourable Angiotensin -7 has emerged as a new strategy to block detrimental effects of Angiotensin II, alleviating the progression of heart hypertrophy. Thus, an in-depth understanding of this regulatory pathway holds promising therapeutic potential that contributes significantly to develop effective cures for heart failure. There have been several Angiotensin II-degrading enzymes discovered of which prolyl carboxypeptidase (PRCP) is a lysosomal Pro-X carboxypeptidase cleaving Angiotensin II and resulting in Angiotensin 1-7 production at a preferential acidic pH optimum. However, yet insignificant attention has been given to PRCP in term of its cardioprotective functions. In our study, we proposed that PRPC is essentially required to protect hearts from Angiotensin II-mediated hypertrophic responses through the control of Angiotensin II and Angiotensin 1-7 levels. In response to 2 weeks of Angiotensin II infusion, mice with global PRCP loss (PRCP-KO) showed exacerbated cardiac hypertrophy, increased levels of fibrosis, oxidative stress, and apoptotic cells without indication of systolic dysfunction. Interestingly, PRCP loss only caused disruptions in Angiotensin II and Angiotensin 1-7 levels in myocardial tissues but not in plasma. Increased Angiotensin II and decreased Angiotensin 1-7 caused following changes in their downstream signalling targets including upregulated ERK1/2 and less AKT activities, respectively. On the other hand, using associated-adenovirus serotype 9 (AAV9) to overexpress PRCP in PRCP-KO hearts alleviated Angiotensin II-mediated cardiac hypertrophy and remodelling through restoring cardiac Angiotensin II and Angiotensin 1-7 levels. This evidence might indicate the pivotal roles of PRCP in the regulation of cardiac Angiotensin II level to maintain the heart function. In concordance, PRCP depletion in adult rat cardiomyocytes also led to a significant increase in Angiotensin II-induced hypertrophic growth, which was blunted by adenovirus-mediated PRCP overexpression. Furthermore, lack of Mas1 receptor but not Angiotensin II type 2 and bradykinin type 2 receptors blocked the PRCP/Angiotensin 1-7/AKT cascade. In conclusion, these preliminary results have advanced our knowledge about the protective role of PRCP against cardiac hypertrophy through, likely, its regulation of cardiac Angiotensin II system. However, more investigation is required to elucidate the underlying mechanisms.
|Date of Award||1 Aug 2020|
- The University of Manchester
|Supervisor||Xin Wang (Supervisor), Wei Liu (Supervisor) & Liz Fitzgerald (Supervisor)|
- Angiotensin II
- Angiotensin 1-7
- Prolyl Carboxypeptidase (PRCP)