{"doi":"10.7554/elife.88732.1","title":"Reprogramming of the cardiac phosphoproteome in conjunction with proteome and transcriptome creates the enhanced performance and protection circuitry in response to chronic adenylyl cyclase-driven stress","abstract":"Abstract Our previous work demonstrated the existence of a remarkable adaptive paradigm of heart performance and protection in response to the constitutive challenge of marked cardiac-specific overexpression of adenylyl cyclase type 8 (TGAC8). However, the molecular regulatory mechanisms remain elusive. Because PKA signaling is the predominantly activated pathway in the TGAC8 left ventricle (LV) performance and protection circuitry and phosphorylation related pathways were enriched from transcriptome and proteome, we hypothesized that phosphorylation states of numerous proteins are reprogrammed in pathways where the transcriptome and proteome were activated in TGAC8 vs. WT. 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 adult TGAC8 LV at 3-4 months of age, and integrated the phosphoproteome with transcriptome and proteome. Based on differentially regulated phosphoproteins by genotype, numerous stress-response pathways within reprogrammed TGAC8 LV, including PKA, PI3K and AMPK signaling pathways, predicted upstream regulators, e.g., PDPK1, PAK1 and PTK2B, and downstream functions, e.g., cell viability, protein quality control, and metabolism were enriched. In addition to PKA, numerous other kinases and phosphatases were hyper-phosphorylated in TGAC8 vs. WT. Hyper-phosphorylated transcriptional factors in TGAC8 were associated with increased mRNA transcription, and immune responses and metabolic pathways. Combination of the phosphoproteome with its proteome and with the previously published TGAC8 transcriptome enabled the elucidation of which cardiac performance and adaptive protection profiles were coordinately regulated at post-translational modification (PTM) (phosphorylation), translational and transcriptional levels. Many stress-response signaling pathways, i.e., PI3K/AKT, ERK/MAPK and ubiquitin labeling, were consistently enriched and activated in the TGAC8 LV at transcriptional, translational and PTM levels. We verified some results through wet lab experiments. 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.","journal":null,"year":2023,"id":400233,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9434,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":895446,"name":"Khalid Chakir","orcid":null,"position":1,"is_corresponding":false},{"id":55722,"name":"Kirill V. Tarasov","orcid":"0000-0001-7799-4670","position":2,"is_corresponding":false},{"id":875573,"name":"Daniel R. Riordon","orcid":null,"position":3,"is_corresponding":false},{"id":987653,"name":"Maria Grazia Perino","orcid":"0000-0002-9469-8555","position":4,"is_corresponding":false},{"id":988004,"name":"Allwin Jennifa Silvester","orcid":null,"position":5,"is_corresponding":false},{"id":55700,"name":"Edward G. Lakatta","orcid":"0000-0002-4772-0035","position":6,"is_corresponding":false},{"id":828541,"name":"Jia-Hua Qu","orcid":"0000-0003-3912-656X","position":0,"is_corresponding":true}],"reference_count":47,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:20:00.023537Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}