Heart failure and chronic obstructive pulmonary disease are common in Veterans and frequently complicated by pulmonary hypertension and right ventricular failure (RVF). Pharmacologic treatments for RVF are limited. Recent studies suggest that powerful cardioprotective effects are mediated by α1-adrenergic receptors, in particular the α1A-subtype (α1A-AR). Our preliminary data show that chronic stimulation of α1A-ARs (for 2 wk) had major beneficial effects on RV function in two models of RVF induced by pulmonary fibrosis or pulmonary artery constriction (PAC). The therapeutic effect was closely linked to reversal of mitochondrial dysfunction. This renewal project will determine the mechanisms involved in α1A-AR-mediated reversal of mitochondrial dysfunction and reversal of RVF. Moreover, in translational studies using human engineered heart tissue (EHT) we will determine if chronic α1A-AR agonism increases mitochondrial function and increases contraction of human EHT. This renewal project will build on the following recent preliminary results: 1. In a model of RVF induced by PAC, RVF was reversed by chronic treatment with a highly specific α1A- AR agonist at a low dose that did not raise blood pressure. 2. Reversal of RVF involved increased myocardial ATP levels and an increased rate of mitochondrial respiration, which indicated protective effects on mitochondria. 3. We recently reported that contractions of RV myocardium in-vitro are significantly inhibited by the low ATP levels observed in RVF. This suggests that ATP level is a critical determinant of RV function. 4. Reversal of RVF involved increased levels of antioxidant enzymes, decreased levels of reactive oxygen species (ROS), and decreased ROS-modification of muscle proteins. 5. Reversal of RVF also involved reversal of hyperacetylation of multiple proteins. 6. In translational studies, we used human EHT created using human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). We recently reported that the α1A-AR is expressed in human EHT. Moreover, chronic α1A-AR agonism for 2 wk caused increased contraction of human EHT. These novel observations suggest 3 hypotheses that will be tested in 3 Specific Aims: 1. Chronic α1A-AR agonism increases mitochondrial respiration rate and ATP production both by increasing cellular antioxidant defenses and by reversing hyperacetylation of mitochondrial proteins. 2. Recovery of mitochondrial function drives recovery of myofilament contraction and reversal of RVF by a) increased bioenergetic status (e.g. increased ATP level), and b) decreased myofilament damage. 3. Chronic α1A-AR agonism increases mitochondrial and myofilament function of human EHT. Aim 1. Determine the mitochondrial mechanisms driving reversal of RVF by chronic α1A-AR agonism. In the setting of RVF, we will determine the specific mitochondrial processes that are improved by chronic α1A-AR agonism (Aim 1A), and determine the roles played by increased antioxidant defe...