Key result
In mice, administration of AdSiR-MR-1 abolished ANG II-induced upregulation of MR-1 and suppressed cardiac hypertrophy, interstitial fibrosis, and inflammatory cell infiltration.
Why the study?
Does gene silencing of MR-1 using adenovirus-delivered siRNA suppress cardiac hypertrophy induced by angiotensin II in mice?
Does gene silencing of MR-1 using adenovirus-delivered siRNA suppress cardiac hypertrophy induced by angiotensin II in mice?
In vivo gene silencing of MR-1 suppresses angiotensin II-induced cardiac hypertrophy and fibrosis in mice, identifying MR-1 as a potential therapeutic target.
MR-1 silencing merits further preclinical validation in cardiac remodeling; leaves open translation to human angiotensin-driven hypertrophy.
Our previous studies proved that myofibrillogenesis regulator (MR)-1 has a close relationship with cardiac hypertrophy induced by ANG II. In the present study, we developed a recombinant adenoviral vector (AdSiR-MR-1) driving small interfering (si)RNA against MR-1 to evaluate its effect on cardiac hypertrophy in vivo. Cardiac hypertrophy was induced by chronic ANG II infusion in mice; AdSiR-MR-1 was administered via the jugular vein through one bolus injection. Thirteen days after the injection, viral DNA was still detectable in the heart, validating the efficiency of gene transfer. Expression levels of MR-1 mRNA and protein were increased by 2.5-fold in the heart after ANG II infusion; AdSiR-control, which contained a scrambled siRNA sequence, had no effect on them. AdSiR-MR-1 treatment abolished the upregulation of MR-1 induced by ANG II. The silencing effect of AdSiR-MR-1 was observed in many other tissues, such as the liver, lung, and kidney, except skeletal muscle. ANG II-induced cardiac hypertrophy was suppressed in mice treated with AdSiR-MR-1, as determined by echocardiography. Morphological and immnohistochemical examinations revealed that interstitial cardiac fibrosis as well as infiltrating inflammatory cells were increased after ANG II infusion; AdSiR-MR-1 greatly ameliorated these disorders. In ANG II-infused mice, MR-1 silencing also blocked the upregulation of other genes related to cardiac hypertrophy or metabolism of the extracellular matrix. In summary, our results demonstrate the feasibility of MR-1 silencing in vivo and suggest that MR-1 could be a potential new target to treat cardiac hypertrophy induced by ANG II.
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Dai et al. (2010) studied Cardiac hypertrophy. AdSiR-MR-1 (adenoviral vector driving siRNA against MR-1) vs. AdSiR-control (scrambled siRNA sequence) was evaluated on Cardiac hypertrophy and MR-1 expression. In mice, administration of AdSiR-MR-1 abolished ANG II-induced upregulation of MR-1 and suppressed cardiac hypertrophy, interstitial fibrosis, and inflammatory cell infiltration.
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