Open AccessTherapeutic Delivery of Pip4k2c‐Modified mRNA Attenuates Cardiac Hypertrophy and Fibrosis in the Failing Heart
Author(s) -
Magadum Ajit,
Singh Neha,
Kurian Ann Anu,
Sharkar Mohammad Tofael Kabir,
Sultaishat,
Chepurko Elena,
Kaur Keerat,
Żak Magdalena M.,
Hadas Yoav,
Lebeche Djamel,
Sahoo Susmita,
Hajjar Roger,
Zangi Lior
Publication year - 2021
Publication title -
advanced science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.388
H-Index - 100
ISSN - 2198-3844
DOI - 10.1002/advs.202004661
Subject(s) - heart failure , mtorc1 , cardiac function curve , medicine , downregulation and upregulation , muscle hypertrophy , fibrosis , cardiac fibrosis , protein kinase b , endocrinology , myocardial fibrosis , cardiology , cancer research , chemistry , biology , phosphorylation , gene , microbiology and biotechnology , biochemistry
Heart failure (HF) remains a major cause of morbidity and mortality worldwide. One of the risk factors for HF is cardiac hypertrophy (CH), which is frequently accompanied by cardiac fibrosis (CF). CH and CF are controlled by master regulators mTORC1 and TGF‐ β , respectively. Type‐2‐phosphatidylinositol‐5‐phosphate‐4‐kinase‐gamma (Pip4k2c) is a known mTORC1 regulator. It is shown that Pip4k2c is significantly downregulated in the hearts of CH and HF patients as compared to non‐injured hearts. The role of Pip4k2c in the heart during development and disease is unknown. It is shown that deleting Pip4k2c does not affect normal embryonic cardiac development; however, three weeks after TAC, adult Pip4k2c −/− mice has higher rates of CH, CF, and sudden death than wild‐type mice. In a gain‐of‐function study using a TAC mouse model, Pip4k2c is transiently upregulated using a modified mRNA (modRNA) gene delivery platform, which significantly improve heart function, reverse CH and CF, and lead to increased survival. Mechanistically, it is shown that Pip4k2c inhibits TGF β 1 via its N‐terminal motif, Pip5k1 α , phospho‐AKT 1/2/3, and phospho‐Smad3. In sum, loss‐and‐gain‐of‐function studies in a TAC mouse model are used to identify Pip4k2c as a potential therapeutic target for CF, CH, and HF, for which modRNA is a highly translatable gene therapy approach.