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Abstract P307: An Exquisite Cardiac Performance And Protection Package Emerges In Mouse With Cardiac-specific Overexpression Of Adenylyl Cyclase Type 8

Young adult (three-month old) mice with cardiac-specific overexpression of AC type 8 (TGAC8) have a markedly elevated heart rate and markedly enhanced ejection fraction around the clock, mimicking cardiac responses of sympathetic autonomic input during acute exercise on a chronic base, but the TGAC8 mice do not exhibit heart failure or increased mortality up to about a year. Using this incessant young TGAC8 mouse as an ideal model to elucidate a high grade cardiac “Performance and Protection Package” (PPP) in response to chronic cardiac stress, we hypothesized that the TGAC8 heart adjusts to the chronical stress by reprogramming itself at multiple omics scales to code the exquisite cardiac PPP. To this end, we compared three-month old TGAC8 mice and their wildtype (WT) littermates using multiple omics analyses, from transcriptome to proteome, to phosphoproteome. Compared to WT, the phosphorylation level of most proteins was increased in the TGAC8 mice, including transcription factors (TF), kinases and phosphatases that are important in regulating transcription and phosphorylation. Among the 191 TFs identified in phosphoproteome, 91 were increased significantly, in line with the general upregulation in transcriptome. Many important stress response signaling pathways were enriched from phosphoproteome. Wherein, three protein quality control pathways, PI3K/AKT signaling, ERK/MAPK signaling and ubiquitination, were consistently enriched across the three omics scales. Most components in PI3K/AKT signaling pathway were upregulated, especially at protein and phosphorylation levels. Consistently, PI3K/AKT substrate phosphopeptides were increased, and downstream effects and functions of PI3K/AKT signaling were activated, including energy metabolism, protein synthesis, cell growth, cardiovascular functions, and NF-kB mediated functions. In summary, profiling the transcriptome, proteome and phosphoproteome of the TGAC8 heart unraveled the mechanism that controls its PPP. The cardiac overexpression of AC8 activates the AC8-cAMP-PKA axis to increase phosphorylation; widespread phosphorylation of the TFs promotes the transcription of numerous additional molecules that also regulate phosphorylation to reprogram the heart. Thereby, the TGAC8 mouse upregulates many stress response signaling pathways to activate the exquisite cardiac PPP.