{"doi":"10.1161/circulationaha.120.049268","title":"A Phosphatase Anchor Weighs on the Heart","abstract":"A Phosphatase Anchor Weighs on the HeartArticle, see p 948 H ypertrophic growth of the heart in response to pathogenic stress has historically been regarded as a compensatory mechanism to reduce wall stress and maximize ventricular performance.However, epidemiological studies have illustrated that chronic hypertrophy increases the risk of poor outcomes in patients with cardiovascular disease, and in preclinical models of heart failure (HF), suppression of hypertrophy is beneficial rather than detrimental. 1As such, there is great interest in defining the molecular underpinnings of cardiomyocyte hypertrophy to facilitate the development of targeted antihypertrophic therapies for HF.In 1998, Molkentin, Olson, and colleagues 2 published a landmark article describing a crucial role for the Ca 2+ /calmodulin-dependent protein phosphatase, calcineurin, in the control of pathological cardiac hypertrophy.Before this discovery, calcineurin had primarily been studied in lymphocytes, where it promotes cellular activation through dephosphorylation of the nuclear factor of activated T cells (NFAT) transcription factor. 3Enthusiasm for the discovery of the link between calcineurin signaling and hypertrophy was bolstered by the existence of agents that inhibit calcineurin catalytic activity, such as the immunosuppressants FK506 and cyclosporine A, suggesting potential repurposing of these drugs to treat HF.However, given the diverse actions of calcineurin in immune as well as nonimmune cells, it is now widely accepted that selective inhibition of calcineurin in cardiomyocytes will be better tolerated and more efficacious than systemic inhibition in patients with HF.Thus, there is a need to better understand the molecular details of calcineurin regulation in the heart to illuminate cardiac-specific approaches for targeting this phosphatase as an antihypertrophic therapy for HF.Calcineurin exists as a heterodimer consisting of a catalytic subunit (CaNA) and a 19-kDa regulatory subunit (CaNB).Of the 3 CaNA isoforms (α, β and γ), CaNAβ appears to be the most important for the development of cardiac hypertrophy. 4inding of Ca 2+ to CaNB enables binding of a Ca 2+ /calmodulin complex to CaNA, thereby releasing autoinhibition and freeing the enzyme to dephosphorylate downstream substrates. 5As detailed below, in the current issue of Circulation, Li et al 6 describe the discovery of a CaNAβ binding protein, CDC42 interacting protein 4 (CIP4), which functions as a scaffold to sequester a pool of calcineurin near the sarcolemma of cardiomyocytes, where it regulates prohypertrophic signaling.The findings have important implications for understanding how cardiac calcineurin is selectively activated by stress signals as opposed to the Ca 2+ that floods cardiomyocytes during each contractile cycle.Furthermore, the data provide proof-ofconcept for an innovative therapeutic approach whereby CIP4 anchoring activity is selectively inhibited to block the action of a small, pathogenic cache of calcineurin as a means of treating HF.","journal":"Circulation","year":2020,"id":124026,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9535,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":433706,"name":"Joshua G. Travers","orcid":"0000-0002-5660-2620","position":1,"is_corresponding":false},{"id":45204,"name":"Timothy A. McKinsey","orcid":"0000-0001-7778-4470","position":2,"is_corresponding":false},{"id":488806,"name":"Kathleen C. Woulfe","orcid":"0000-0001-9885-7026","position":0,"is_corresponding":true}],"reference_count":13,"raw_metadata":null,"created_at":"2026-07-18T23:15:03.403566Z","pmid":"32897751","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":[]}