A remarkable adaptive paradigm of heart performance and protection emerges in response to the constitutive challenge of marked cardiac-specific overexpression of adenylyl cyclase type 8

Tarasov, Kirill V.; Chakir, Khalid; Riordon, Daniel R.; Lyashkov, Alexey E.; Ahmet, Ismayil; Perino, Maria Grazia; Silvester, Allwin J.; Wang, Mingyi; Lukyanenko, Yevgeniya O.; Qu, Jia-Hua; Barrera, Miguel C.-R.; Tarasova, Yelena S.; Pacák, Karel; Field, Loren J.; Lakatta, Edward G.

doi:10.1016/j.bpj.2022.11.2844

Cited by 4 publications

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“…In contrast, many fewer phosphatases were predicted between TGAC8 and WT, and most of these were predicted to be inhibited (Figure 4E and File 9). Thus, the differential genotypic enrichment of phosphorylation status and predicted activation of kinases and phosphatases identified in our post hoc analysis of our previously reported TGAC8 vs. WT transcriptome 10 are linked to the differential genotypic reprogramming of the phosphoproteome discovered in the present study.…”

Section: Resultssupporting

confidence: 63%

“…Because kinases and phosphatases are the key regulators of phosphorylation, and phosphorylation of transcriptional factors (TFs) are the primary determinant of their activities in transcription, we compared genotypic differences in kinases, phosphatases and TFs within the phosphoproteome and proteome with our previously published genotypic differences in the TGAC8 vs. WT transcriptome 10 (Figure 3E). We identified 196 kinases, 71 phosphatases and 191 TFs in the present phosphoproteome (Figure 3F).…”

Section: Resultsmentioning

confidence: 99%

“…The processed transcriptomic data were obtained from our recently published work 10 . The significantly changed mRNAs (TGAC8 vs. WT, q-value < 0.05) were uploaded into DAVID 2 (version: 6.8; https://david.ncifcrf.gov/home.jsp) for Gene Ontology (GO) term enrichments, and were also imported into Ingenuity Pathway Analysis 3 (IPA (QIAGEN, March 2020)) for upstream kinases and phosphatases prediction.…”

Section: Methodsmentioning

confidence: 99%

“…It is of utmost importance to unravel how the TGAC8 adapts the heart to this chronic stress, as this knowledge can be applied to the study of cardiac physiology and pathology and even to develop treatments for cardiovascular diseases (CVDs). In this regard, as a first “port-of-call”, we had recently compared the LV transcriptome and proteome in TGAC8 and WT littermates 10 . Because PKA signaling pathway was highly enriched in TGAC8 vs. WT, we reasoned that protein phosphorylation will differ between TGAC8 and WT, and the phosphorylation modification will play a crucial role in the remarkable adaptation capacity of the TGAC8 heart in response to markedly increased AC8-cAMP-PKA-Ca 2+ signaling.…”

Section: Introductionmentioning

confidence: 99%

“…Because PKA signaling pathway was highly enriched in TGAC8 vs. WT, we reasoned that protein phosphorylation will differ between TGAC8 and WT, and the phosphorylation modification will play a crucial role in the remarkable adaptation capacity of the TGAC8 heart in response to markedly increased AC8-cAMP-PKA-Ca 2+ signaling. We have assessed the concordance of the genotypic differences at the phosphorylation level to some degree in western blot (WB) experiments 10 .…”

Section: Introductionmentioning

confidence: 99%

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Reprogramming of cardiac phosphoproteome, proteome and transcriptome confers resilience to chronic adenylyl cyclase-driven stress

Chakir

Tarasov

et al. 2022

Preprint

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An appropriate intensity and duration of increased AC-cAMP-PKA-Ca2+ signaling is the quintessential component of acute adaptation to cardiac stress. Our previous work demonstrated the existence of an exquisite heart performance and protection profile in response to chronically increased cardiac AC-cAMP-PKA-Ca2+ signaling in young adult mice with cardiac-specific overexpression of adenylyl cyclase type 8 (AC8) (TGAC8). Here, we conducted an unbiased phosphoproteomics analysis in order to determine the role of altered protein phosphorylation in the chronic adaptive heart performance and protection profile of left ventricle (LV) of adult TGAC8 at 3-4 months of age. We identified 12,963 phospho-peptides and 3646 phosphoproteins, including 4990 upregulated phosphopeptides and 781 differentially regulated (741 Up and 40 Down) phosphoproteins in TGAC8 vs. WT. Based on differentially regulated phosphoproteins by genotype, we discovered the enrichment of numerous stress response canonical pathways within reprogrammed TGAC8 LV, including protein kinase A (PKA) signaling, PI3K signaling, and AMPK signaling, predicted upstream regulators, e.g., PDPK1, PAK1 and PTK2B, and downstream functions, e.g., cell viability, protein quality control, and metabolism. In addition to PKA, numerous kinases (83) and phosphatases (30) were hyper-phosphorylated in TGAC8 vs. WT. By combining the phosphoproteome with its proteome and with the previously published TGAC8 transcriptome, we determined which cardiac performance and adaptive protection profiles were coordinately regulated at post-translational modification (PTM) (phosphorylation), translational and transcriptional levels. In order to assess the impact of phosphorylation on mRNA transcription, we determined the phosphorylation states of transcriptional factors (TFs) that differed by genotype. Hyper-phosphorylated TFs in TGAC8 were associated with increased mRNA transcription, and immune responses and metabolism pathways. To determine the coordination of proteome and phosphoproteome in reprogramming the TGAC8 LV, we normalized its phosphoproteome to its proteome (by dividing the protein phosphorylation abundance by protein abundance). In functional enrichment analysis of 229 normalized phosphoproteins that were differentially regulated by genotype, enriched IPA canonical pathways in the phosphoproteome of TGAC8 LV before and after normalization showed high consistency. The combination of aforementioned analyses indicated that many stress response signaling pathways, i.e., PI3K/AKT signaling and ubiquitin labeling, were consistently enriched at transcriptional, translational and PTM levels, and that PI3K/AKT signaling was also activated in the TGAC8 LV. Thus, PTM of protein by phosphorylation, per se, contributes immensely to the heart performance and protection profile of TGAC8 LV, and is coordinately regulated with altered transcription and translation in the TGAC8 to activate critical stress response pathways.

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Section: Resultssupporting

confidence: 63%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Reprogramming of cardiac phosphoproteome, proteome and transcriptome confers resilience to chronic adenylyl cyclase-driven stress

Chakir

Tarasov

et al. 2022

Preprint

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Metabolism configures immune response across multi-systems: Lessons from COVID-19

Gupta,

Najumuddin,

Rajendran

et al. 2023

Advances in Biological Regulation

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Cardiac Specific Overexpression of Adenylyl Cyclase 8 Reprograms the Mouse Sinoatrial Node Transcriptome

Qu,

Tarasov,

Chakir

et al. 2023

Preprint

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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 Ca2+/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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A remarkable adaptive paradigm of heart performance and protection emerges in response to the constitutive challenge of marked cardiac-specific overexpression of adenylyl cyclase type 8

Cited by 4 publications

References 0 publications

Reprogramming of cardiac phosphoproteome, proteome and transcriptome confers resilience to chronic adenylyl cyclase-driven stress

Reprogramming of cardiac phosphoproteome, proteome and transcriptome confers resilience to chronic adenylyl cyclase-driven stress

Metabolism configures immune response across multi-systems: Lessons from COVID-19

Cardiac Specific Overexpression of Adenylyl Cyclase 8 Reprograms the Mouse Sinoatrial Node Transcriptome

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