Abstract 2276: Differential Modulation of Mitochondrial Function in Doxorubicin Cardiotoxicity by beta2-Adrenergic Receptors is Strain Dependent: Role of mtDNA
β2-Adrenergic Receptors (β2-ARs) play an important role in cardioprotection through crosstalk with diverse signaling pathways. We have previously shown that β2-AR signaling positively modulates pro-survival kinases and ameliorates mitochondrial dysfunction during doxorubicin (DOX) cardiotoxicity. Administration of DOX to β2−/− mice, or in WT mice with the β2-antagonist ICI 118,551, dramatically increases acute cardiotoxicity. We explored whether this effect was strain specific by generating β2−/− mice on two congenic strains: FVB/N and C57BL/6J. DOX was administered to β2−/− mice, to strain-matched WT controls, and to WT given ICI 118,551. When DOX was given to WT FVB or C57, there was no acute cardiotoxicity; pretreatment with ICI increased mortality to 85% in FVB but had no effect in C57. Similarly, there was 100% mortality in FVB β2−/−, but 0% in C57 β2−/−. To test the role of mitochondrial DNA (mtDNA) in this strain effect, FVB females were backcrossed with C57 males and vice versa. F1s obtained from these crosses have mixed FVBxC57 nuclear DNA and either only FVB or C57 mtDNA, depending on maternal strain. Mice from each backcross were given ICI prior to DOX. Those with FVB mtDNA had significantly higher mortality (67%) compared with those with C57 mtDNA (31%). This was confirmed by repeating this experiment with β2−/− (92% mortality for FVB mtDNA vs. 47% for C57 mtDNA). Sequence analysis of mtDNA of these two strains revealed a single mtDNA missense mutation (G7778T) in FVB, resulting in an amino acid change (Tyr to Asp) in a highly conserved region of ATP8, a subunit of the complex V ATP synthase. Mitochondrial complex activity was similar for complex I, II3III and IV in FVB vs. C57, but mitochondrial respiration was decreased in FVB to 65% of that of C57, indicating a decrease in complex V ATP synthesis in FVB. These data suggest that β2-ARs modulate mitochondrial function in DOX cardiotoxicity in a strain specific manner, mediated in part by differential activity of ATP synthase. mtDNA-derived strain differences may explain the reported variability in response to cardiac stressors in other murine models of cardiovascular disease and suggests that attention be paid to maternal origin in developing congenic strains for research.