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Molecular Network Approach Reveals Rictor as a Central Target of Cardiac ProtectomiRs.

ABSTRACT: Cardioprotective medications are still unmet clinical needs. We have previously identified several cardioprotective microRNAs (termed ProtectomiRs), the mRNA targets of which may reveal new drug targets for cardioprotection. Here we aimed to identify key molecular targets of ProtectomiRs and confirm their association with cardioprotection in a translational pig model of acute myocardial infarction (AMI). By using a network theoretical approach, we identified 882 potential target genes of 18 previously identified protectomiRs. The Rictor gene was the most central and it was ranked first in the protectomiR-target mRNA molecular network with the highest node degree of 5. Therefore, Rictor and its targeting microRNAs were further validated in heart samples obtained from a translational pig model of AMI and cardioprotection induced by pre- or postconditioning. Three out of five Rictor-targeting pig homologue of rat ProtectomiRs showed significant upregulation in postconditioned but not in preconditioned pig hearts. Rictor was downregulated at the mRNA and protein level in ischemic postconditioning but not in ischemic preconditioning. This is the first demonstration that Rictor is the central molecular target of ProtectomiRs and that decreased Rictor expression may regulate ischemic postconditioning-, but not preconditioning-induced acute cardioprotection. We conclude that Rictor is a potential novel drug target for acute cardioprotection.

SUBMITTER: Makkos A

PROVIDER: S-EPMC8430799 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The objective of the present study was to 1) analyze the ascending aortic proteome within a mouse model of Marfan syndrome (MFS; Fbn1C1041G/+) at early and late stages of aneurysm and 2) subsequently test a novel hypothesis formulated on the basis of this unbiased proteomic screen that links changes in integrin composition to transforming growth factor (TGF)-β-dependent activation of the rapamycin-independent component of mammalian target of rapamycin (Rictor) signaling pathway. Ingenuity Pathway Analysis of over 1,000 proteins quantified from the in vivo MFS mouse aorta by data-independent acquisition mass spectrometry revealed a predicted upstream regulator, Rictor, that was selectively activated in aged MFS mice. We validated this pattern of Rictor activation in vivo by Western blot analysis for phosphorylation on Thr1135 in a separate cohort of mice and showed in vitro that TGF-β activates Rictor in an integrin-linked kinase-dependent manner in cultured aortic vascular smooth muscle cells. Expression of β3-integrin was upregulated in the aged MFS aorta relative to young MFS mice and wild-type mice. We showed that β3-integrin expression and activation modulated TGF-β-induced Rictor phosphorylation in vitro, and this signaling effect was associated with an altered vascular smooth muscle cell proliferative-migratory and metabolic in vitro phenotype that parallels the in vivo aneurysm phenotype in MFS. These results reveal that Rictor is a novel, context-dependent, noncanonical TGF-β signaling effector with potential pathogenic implications in aortic aneurysm. NEW & NOTEWORTHY We present the most comprehensive quantitative analysis of the ascending aortic aneurysm proteome in Marfan syndrome to date resulting in novel and potentially wide-reaching findings that expression and signaling by β3-integrin constitute a modulator of transforming growth factor-β-induced rapamycin-independent component of mammalian target of rapamycin (Rictor) signaling and physiology in aortic vascular smooth muscle cells.

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Molecular Network Approach Reveals Rictor as a Central Target of Cardiac ProtectomiRs.

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