Preemptive heme oxygenase-1 gene delivery reveals reduced mortality and preservation of left ventricular function 1 yr after acute myocardial infarction

Abstract

-We reported previously that predelivery of heme oxygenase-1 (HO-1) gene to the heart by adenoassociated virus-2 (AAV-2) markedly reduces ischemia and reperfusion (I/R)-induced myocardial injury. However, the effect of preemptive HO-1 gene delivery on long-term survival and prevention of postinfarction heart failure has not been determined. We assessed the effect of HO-1 gene delivery on long-term survival, myocardial function, and left ventricular (LV) remodeling 1 yr after myocardial infarction (MI) using echocardiographic imaging, pressure-volume (PV) analysis, and histomorphometric approaches. Two groups of Lewis rats were injected with 2 ϫ 10 11 particles of AAV-LacZ (control) or AAV-human HO-1 (hHO-1) in the anterior-posterior apical region of the LV wall. Six weeks after gene transfer, animals were subjected to 30 min of ischemia by ligation of the left anterior descending artery followed by reperfusion. Echocardiographic measurements and PV analysis of LV function were obtained at 2 wk and 12 mo after I/R. One year after acute MI, mortality was markedly reduced in the HO-1-treated animals compared with the LacZ-treated animals. PV analysis demonstrated significantly enhanced LV developed pressure, elevated maximal dP/dt, and lower end-diastolic volume in the HO-1 animals compared with the LacZ animals. Echocardiography showed a larger apical anterior-to-posterior wall ratio in HO-1 animals compared with LacZ animals. Morphometric analysis revealed extensive myocardial scarring and fibrosis in the infarcted LV area of LacZ animals, which was reduced by 62% in HO-1 animals. These results suggest that preemptive HO-1 gene delivery may be useful as a therapeutic strategy to reduce post-MI LV remodeling and heart failure.

Oxidative stress-inducible lentiviral vectors for gene therapy

“…5 Nevertheless, HO-1 has been used for gene therapy in several experimental animal models of CVD. 10,11,27,28 In the study by Pachori et al 10 Oxidative stress-inducible vectors H Hurttila et al significant induction of endogenous HO-1 was observed, yet HRE-regulated HO-1 overexpression provided an additional benefit. In our study, both in controls as well as 2 Â GCLM-HO-1-transduced HUVECs, 15d-PGJ 2 significantly attenuated TNF-a-induced NF-kB activation and VCAM-1 expression, but the effect was greater in HO-1-transduced cells (Figure 6).…”

Two Novel Approaches Providing Cardiac Protection Against Oxidative Stress

“…Preclinical studies for ischemic heart disease employing antioxidants although still at an early stage have shown some promise (Sugamura and Keaney, 2011;Bolli et al, 2004;Cannon, 2005). For example heme oxygenase -1 (HO-1) based gene therapy has been proposed as a therapeutic strategy for ischemic heart disease because the enzyme has a clear antioxidant capacity (Liu et al, 2007). In addition, the products of heme metabolism, carbon monoxide and bilirubin have been reported to possess cytoprotective properties (Poss and Tonegawa, 1997;Stocker et al, 1987).…”

“…Cardiac function is compromised in patients that survive an initial ischemic event and this progressive myocardial impairment leads to heart failure (Liu et al, 2007;Sugamura and Keaney, 2011;Jessup and Brozena, 2003). High levels of reactive oxygen species (ROS) contribute to the process of disease progression in both myocardial ischemia and in models of heart failure.…”

Heme Oxygenase-1 Induction Enhances Cell Survival and Restores Contractility to Unvascularized Three-Dimensional Adult Cardiomyocyte Grafts ImplantedIn Vivo

“…13,14 Biliverdin and its endproduct, bilirubin, are both potent antioxidants with demonstrated cell-protective effects in ischemia-reperfusion injury. [15][16][17][18] Importantly, besides these key roles in cell survival, HO-1 has additional, complementary effects that are pro-angiogenic, [19][20][21] antiinflammatory, 8,9,18,[22][23][24] and anti-fibrotic, 12,23,[25][26][27] all of which would be highly desirable in implanted engineered tissues.…”