Gene therapy with hypoxia-inducible factor 1 alpha in skeletal muscle is cardioprotective in vivo

Protecting the heart through delivering DNA encoding for heme oxygenase-1 into skeletal muscle

“…We did not address the mechanism of action evoking protection in the current study, as determining mechanisms in vivo is scientifically cumbersome and often leads to unconvincing results. We have previously seen that serum bilirubin increases when mice are treated with HIF-1α in the skeletal muscle (Czibik et al, 2011). We have also shown that treating HL-1 cells with HIF-1α, HMOX-1, carbon monoxide donors, or bilirubin protects against induced injury (Czibik et al, 2009b).…”

“…However, this is an invasive procedure due to the hearts' protective placement in the thorax and is thus unlikely to represent a large-scale clinical treatment. A systemic delivery through use of viral vectors is another approach with a high likelihood of success, but with many challenges (Czibik et al, 2011). Use of viral vectors could result in systemic dissemination and inappropriate inflammatory responses, which could be life-threatening.…”

“…Transthoracic echocardiography was performed with a Vevo 770 High-Resolution In Vivo Imaging System (VisualSonics, Toronto, ON, Canada) using a high-frequency ultrasound probe (RMV-707B) as described elsewhere (Czibik et al, 2011;Huusko et al, 2010). Twodimensional guided M-mode recordings of the left ventricle (LV) in the short and long axes viewed at the level of the papillary muscle were recorded.…”

“…The main implication of the current study is the "proof of principle"; that treatment of a remote organ can protect other organs. Remote cardiac protection by DNA delivery has previously been evoked through delivery of insulin-like growth factor I (Lai et al, 2012) or vascular endothelial growth factor 1 (Zisa et al, 2009) into the skeletal muscle, as well as HIF-1α (Czibik et al, 2009a(Czibik et al, , 2009b(Czibik et al, , 2011. Even bone marrow derived stem cells have been delivered into the skeletal muscle to achieve myocardial protection (Shabbir et al, 2009).…”

“…Gene delivery of hypoxia-inducible factor 1 alpha (HIF-1α) into the skeletal muscle protects against acute and chronic ischemic injury of the heart in vivo, ex vivo, and in vitro (Czibik et al, 2009a(Czibik et al, , 2009b(Czibik et al, , 2011. HIF-1α was detected at the site of injection from 1 to 8 weeks later, and not in any other organ (Czibik et al, 2009b).…”