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Ziegler, Tilman; Bähr, Andrea; Howe, Andrea; Klett, Katharina; Husada, Wira; Weber, Christian; Laugwitz, Karl-Ludwig; Kupatt, Christian; Hinkel, Rabea (2018): T beta 4 Increases Neovascularization and Cardiac Function in Chronic Myocardial Ischemia of Normo- and Hypercholesterolemic Pigs. In: Molecular Therapy, Vol. 26, No. 7: pp. 1706-1714
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Translations of new therapeutic options for cardiovascular disease from animal studies into a clinical setting have been hampered, in part by an improper reflection of a relevant patient population in animal models. In this study, we investigated the impact of thymosin beta 4 (T beta 4), which promotes collateralization and capillarization, during hypercholesterolemia, a known risk factor of coronary artery disease. Initial in vitro results highlighted an improved endothelial cell function upon T beta 4 treatment under control conditions and during hypercholesterolemic stress (scratch area [pixels]: oxidized low-density lipoprotein [oxLDL], 191,924 +/- 7,717;and oxLDL + T beta 4, 105,621 +/- 11,245). To mimic the common risk factor of hypercholesterolemia in vivo, pigs on regular (NC) or high-fat (HC) diet underwent chronic myocardial ischemia followed by recombinant adeno-associated virus (rAAV)-mediated transduction of T beta 4 or LacZ as a control. We show that T beta 4 overexpression improves capillarization and collateralization (collaterals: NC + rAAV.LacZ, 2.1 +/- 0.5;NC + rAAV.T beta 4, 6.7 +/- 0.5;HC + rAAV.LacZ, 3.0 +/- 0.3;and HC + rAAV.T beta 4, 6.0 +/- 0.4), ultimately leading to an improved myocardial function in both diet groups (ejection fraction [EF] at day 56 [%]: NC + rAAV.LacZ, 26 +/- 1.1;NC + rAAV.T beta 4, 45 +/- 1.5;HC + rAAV.LacZ, 26 +/- 2.5;and HC + rAAV.T beta 4, 41 +/- 2.6). These results demonstrate the potency of T beta 4 in a patient-relevant large animal model of chronic myocardial ischemia.