Key result
Cardiac-specific overexpression of AC8 reprogrammed the mouse sinoatrial node transcriptome, downregulating OXPHOS and ribosome pathways while upregulating inositol phosphate signaling.
Why the study?
The sinoatrial node transcriptomic regulation underlying the chronic shift in heart rate and heart rate variability in mice overexpressing AC8 had not been delineated.
Does cardiac-specific overexpression of Adenylyl Cyclase 8 alter the sinoatrial node transcriptome in mice?
Does cardiac-specific overexpression of Adenylyl Cyclase 8 alter the sinoatrial node transcriptome in mice?
p-value: p=<0.05
Cardiac-specific overexpression of AC8 in mice reprogrammed the sinoatrial node transcriptome, downregulating mitochondrial and ribosomal pathways while upregulating inositol phosphate signaling, suggesting a molecular cost for the chronically elevated heart rate.
AC8 overexpression elevates HR in mice; leaves open whether targeting the coupled-clock system will translate to human rate or rhythm disorders.
A coupled-clock system intrinsic to sinoatrial node (SAN) pacemaker cells that regulates the rate and rhythm of spontaneous action potential firing, is activated by Ca 2+ /calmodulin-stimulated Adenylyl Cyclase (AC) types 8 and 1. Our previous work in mice with cardiac specific overexpression of human AC8 gene (TGAC8) discovered that compared to its wild-type (WT) littermates, the heart rate (HR) of TGAC8 is elevated (by about 30%, 24 hours a day, 7days a week), and that the TGAC8 heart rhythm is markedly coherent, i.e., the HR Variability (HRV) lacks complexity, similar to that associated with aging or cardiac pathology. Reprogramming of molecular mechanisms, particularly SAN transcriptomic regulation that underlies the remarkable chronic shift in HR and HRV, however, has not been delineated. We conducted deep RNA sequencing (RNA-seq) in TGAC8 and WT SANs, using Mm10plus with human ADCY8 DNA sequence as the reference genome. Utilizing multiple bioinformatic techniques, we not only profiled the expression of marker genes related to SAN functions and AC-cAMP-PKA signaling, but also discovered negatively enriched hub pathways that differed in TGAC8 vs. WT, the top three being OXPHOS, ribosome, and cardiac muscle contraction. In contrast, signaling pathways related to inositol phosphate and its metabolism were positively enriched in TGAC8. Further, we identified two transcription regulators, KDM5A and PPARGC1A, that mediate effects of TGAC8 on ribosome and mitochondria. In summary, reprogrammed transcriptional regulation increases the HR of TGAC8 at the cost of impairment of other SAN cell functions, i.e., altered ribosome and inositol phosphate signaling and its crosstalk with mitochondria. Because these cell signaling alterations are associated with cardiac aging and age-associated CVDs, the TGAC8 mouse appears to be an ideal model in which to probe for potential therapeutic targets for cardiac aging and age-associated CVDs.
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Qu et al. (2023) studied Cardiac aging and age-associated cardiovascular diseases (animal model) (n=11). Cardiac-specific overexpression of human AC8 gene (TGAC8) vs. Wild-type (WT) littermates was evaluated on Differentially expressed genes in the sinoatrial node transcriptome (p=<0.05). Cardiac-specific overexpression of AC8 reprogrammed the mouse sinoatrial node transcriptome, downregulating OXPHOS and ribosome pathways while upregulating inositol phosphate signaling.
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