miR-301a-PTEN-AKT Signaling Induces Cardiomyocyte Proliferation and Promotes Cardiac Repair Post-MI

Abstract

Adult hearts are hard to recover after cardiac injury due to the limited proliferative ability of cardiomyocytes. Emerging evidence indicates the induction of cell cycle reentry of cardiomyocytes by special treatment or stimulation, which offers adult heart regenerative potential. Herein, a microRNA (miRNA) screening in cardiomyocytes identified miR-301a enriched specially in the neonatal cardiomyocytes from rats and mice. Overexpression of miR-301a in primary neonatal cardiomyocytes and H9C2 cells induced G 1 /S transition of the cell cycle, promoted cellular proliferation, and protected cardiomyocytes against hypoxia-induced apoptosis. Adeno-associated virus (AAV)9-mediated cardiac delivery of miR-301a to the mice model with myocardial infarction (MI) dramatically promoted cardiac repair post-MI in vivo . Phosphatase and tensin homolog (PTEN)/phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway was confirmed to mediate miR-301a-induced cell proliferation in cardiomyocytes. Loss of function of PTEN mimicked the miR-301a-induced phenotype, while gain of function of PTEN attenuated the miR-301a-induced cell proliferation in cardiomyocytes. Application of RG7440, a small molecule inhibitor of AKT, blocked the function of miR-301a in cardiomyocytes. The current study revealed a miRNA signaling in inducing the cell cycle reentry of cardiomyocytes in the injured heart, and it demonstrated the miR-301a/PTEN/AKT signaling as a potential therapeutic target to reconstitute lost cardiomyocytes in mammals.

LKB1IP promotes pathological cardiac hypertrophy by targeting PTEN/Akt signalling pathway

“…During the development of cardiac hypertrophy, PTEN is modulated and plays a vital role. Suppression of PTEN by miR‐301a could promote cardiomyocytes proliferation 30 . Tripartite motif 10 (TRIM10) promoted ubiquitination of PTEN, consequently resulting in its proteasomal degradation and activation of hypertrophic signalling 31 .…”

“…PTEN expression is regulated by many transcription factors such as the zinc-finger transcription factor sal-like protein 416 and the transacting EMT transcription factor SNAIL (also known as SNAI1)17 as well as microRNAs such as miR-19 in Cowden and leukaemia disease,18,19 the miR-17-92 cluster in lymphoproliferative disease,20 miR-21 in multiple cancers and metabolic and inflammatory diseases 21,22. PTEN function can be modulated by its interacting proteins such as Na + /H PTEN is modulated and plays a vital role.Suppression of PTEN by miR-301a could promote cardiomyocytes proliferation 30. Tripartite motif 10 (TRIM10) promoted ubiquitination of PTEN, consequently resulting in its proteasomal degradation and activation of hypertrophic signalling 31.…”

Cardiomyocyte Proliferation as a Source of New Myocyte Development in the Adult Heart

“…More specifically, miR-199a-3p downregulates YAP inhibitory kinase, TAOK1, and the E3 ubiquitin ligase, β-TrCP, to inhibit YAP degradation, and also represses Cofilin2 to maintain YAP nuclear localization [73]. PTEN/PI3K/AKT is another signal transduction pathway that is activated by miR-301a to promote cardiomyocyte re-entry into the cell cycle; miR-301a suppresses PTEN to activate AKT and induce expression of cell cycle genes such as cyclin D1, in cardiac myocytes [50]. Other miRNAs have been reported to promote cell cycle progression in cardiomyocytes by targeting the TBX1/JAK2/STAT1 pathway [74], the NFkB pathway [75], or signaling molecules such as the cell cycle inhibitors Wee1 [76] and Bim [77], among others [78,79].…”

Comprehensive analysis to identify DLEU2L/TAOK1 axis as a prognostic biomarker in hepatocellular carcinoma

“…Phosphatase and tensin homolog (PTEN) is a very commonly mutated tumor suppressor gene in human cancers, including HCC. 26 , 27 , 28 , 29 Accumulating evidence has shed light on PTEN activity, which can be regulated by mutations, epigenetic silencing, abnormal protein, transcriptional inhibition, localization, and posttranslational modification. 30 , 31 , 32 At the same time, some data have indicated that decreased PTEN expression is a common event in HCC and is associated with disease stage, tumor grade and size, and increased expression of tumor markers.…”