The heart as an endocrine source of metabolic vasodilators (1079.26)

Abstract

During heightened cardiac work, O2 consumption by the heart increases. This increase benefits energy production via mitochondrial e¯ transport, but the process of e¯ transport is not perfect and some e¯ “leak” from respiratory chain and reduce O2. This reduction yields O2˙¯, which reacts with thiol groups, iron, and is rapidly metabolized into H2O2 by mitochondrial superoxide dismutase (SOD2). To understand the potential systemic effects of the metabolic dilator, H2O2, we studied mice with cardiac specific SOD2 overexpression, which would increase the amount of H2O2 produced by the heart. To determine if this enhanced production of H2O2 results in a humoral action, i.e., systemic vasodilation, we first evaluated the effectiveness of SOD2 overexpression to effectively remove O2˙¯ from the mitochondria (EPR). SOD2 transgenic mice produced less O2, and had lower redox activity. Mitochondria of SOD2‐tg (vs WT) had lower GSSG concentration (decreased by 37.2±4.5%, GSH/GSSG ratio was increased by 66.7±6.8%). EPR analysis of the isolated mitochondria showed significant decrease of semiquinone in the SOD2‐tg vs WT at the Qi site (by 69.4±9.9%), and a diminished complex I protein thiyl radical(s) in the mitochondria of SOD2‐tg. These results support a more reducing milieu in the mitochondria of the SOD2‐tg heart. Cardiac mitochondria isolated from SOD2‐tg exhibited no significant differences in the respiratory control index between WT and SOD2‐tg (6.30.3 vs. 5.70.5, p>0.05). These results support the concept that the SOD2 overexpression is effective and results in increased production of H2O2. Moreover, arterial pressure was lower in the SOD2‐tg, but was normalized by iv injection of catalase, implying that the metabolic dilator, H2O2, “spilled” over inducing systemic vasodilation. In conclusion, SOD2 overexpression in myocytes triggers a more reductive milieu in murine heart enhancing the production of H2O2, which then acts as an endocrine dilator causing reductions in arterial pressure.Grant Funding Source: NIH RO1 HL083237