Abstract
Myeloid cell leukemia 1 (Mcl1), an abundant protein in the myocardium, plays an essential role in fibrosis and anti-inflammation in cardiomyocytes to prevent heart failure. However, whether Mcl1 3′-untranslated regions (3′-UTR) has the cardio-protecting function remains unclear. Down-regulation of Mcl1 was observed in adult mice heart tissues after Angiotensin II (Ang II) treatment. Consistent with in vivo results, the reduction of Mcl1 expression was identified in Ang II-treated neonatal cardiomyocytes. Mechanistically, Mcl1 3′-UTR prevented Ang II-induced cardiac apoptosis via up-regulation of Mcl1 and an angiogenic factor with a G-patch domain and a forkhead-associated domain 1 (Aggf1), which plays cardiac-protective role. Our work broadens the scope of gene therapy targets and provides a new insight into gene therapy strategies involving mRNAs’ 3′-UTRs application.
Highlights
Hypertension contributes significantly to cardiovascular morbidity and mortality (Delles et al, 2010)
Consistent with previously reported, the systolic blood pressure (SBP) of Angiotensin II (Ang II)-infused group was significantly increased (Figure 1A). Echocardiography showed that both left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) in Ang II-infused mice were significantly decreased compared with vehicle group (Figure 1B)
We found that the reduction of Aggf1 along with alleviated Myeloid cell leukemia 1 (Mcl1) in hearts from Ang II-infused mice and isolated cardiomyocytes treated with Ang II
Summary
Hypertension contributes significantly to cardiovascular morbidity and mortality (Delles et al, 2010). As one of the major risk factors for cardiovascular diseases, hypertension causes cardiac dysfunction with cardiac inflammation and fibrosis, accompanied with cardiomyocyte apoptosis (Brooks et al, 2010; Jia et al, 2012). Loss of Mcl in the adult heart leads to early contractile dysfunction in cardiac hypertrophy, fibrosis and inflammation, resulting in rapid heart failure (Thomas and Gustafsson, 2013; Wang et al, 2013). Mcl deficiency did not significantly increase caspase-activation or poly ADPribose polymerase (Parp) cleavage, it is critical for normal mitochondrial function (Thomas and Gustafsson, 2013; Wang et al, 2013). Maintaining endogenous levels of Mcl in pathological conditions could support clearance of damaged organelles and improve cardiac outcomes
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