Diverging targets mediate the pathological role of miR-199a-5p and miR-199a-3p by promoting cardiac hypertrophy and fibrosis

Abstract

MicroRNA-199a-5p (miR-199a-5p) and -3p are enriched in the myocardium, but it is unknown whether miR-199a-5p and -3p are co-expressed in cardiac remodeling and what roles they have in cardiac hypertrophy and fibrosis. We show that miR-199a-5p and -3p are co-upregulated in the mouse and human myocardium with cardiac remodeling and in Ang-II-treated neonatal mouse ventricular cardiomyocytes (NMVCs) and cardiac fibroblasts (CFs). miR-199a-5p and -3p could aggravate cardiac hypertrophy and fibrosis in vivo and in vitro . PPAR gamma coactivator 1 alpha (Ppargc1a) and sirtuin 1 (Sirt1) were identified as target genes to mediate miR-199a-5p in promoting both cardiac hypertrophy and fibrosis. However, miR-199a-3p aggravated cardiac hypertrophy and fibrosis through targeting RB transcriptional corepressor 1 (Rb1) and Smad1, respectively. Serum response factor and nuclear factor κB p65 participated in the upregulation of miR-199a-5p and -3p in Ang-II-treated NMVCs and mouse CFs, and could be conversely elevated by miR-199a-5p and -3p. Together, Ppargc1a and Sirt1, Rb1 and Smad1 mediated the pathological effect of miR-199a-5p and -3p by promoting cardiac hypertrophy and fibrosis, respectively. This study suggests a possible new strategy for cardiac remodeling therapy by inhibiting miR-199a-5p and -3p.

MiR‐199a‐5p promotes ferroptosis‐induced cardiomyocyte death responding to oxygen–glucose deprivation/reperfusion injury via inhibiting Akt/eNOSsignaling pathway

“…Thirdly, LY294002 is also used to inhibit AKT/eNOS signaling pathway, siRNA‐mediated the knockdown of AKT or eNOS can be added to observe the function of AKT/eNOS signaling pathway. Finally, based on previous studies, other target genes or signaling pathway, such as HIF‐1α, 36 sirtuin 1 (Sirt1), 18 and ERK, p38, and JNK signaling pathways 40 are the direct target genes/pathway of miR‐199a‐5, which is worth exploring whether these genes play a role in the antiferroptosis of miR‐199a‐5 during myocardial OGD/R injury.…”

“…Among them, miR‐199a‐5p attracted growing interest in the field of oncology, such as cervical cancer, non‐small cell lung cancer, and papillary thyroid carcinoma in the last few years 15,16 . Recently, the researches on the involvement of miR‐199a‐5p in the control of cardiac physiology and in the pathogenesis of heart failure have been revealed 17–19 . Various studies found that myocardial miR‐199‐5p levels are increased under cardiac damage, which is responsible for pathophysiological alterations contributing to the development of heart diseases including myocardial I/R injury 20,21 .…”

“…15,16 Recently, the researches on the involvement of miR-199a-5p in the control of cardiac physiology and in the pathogenesis of heart failure have been revealed. [17][18][19] Various studies found that myocardial miR-199-5p levels are increased under cardiac damage, which is responsible for pathophysiological alterations contributing to the development of heart diseases including myocardial I/R injury. 20,21 Although miR-199-5p is involved in the progression of I/R-induced myocardial injury, whether miR-199-5p synergistically functions in the ferroptosis-induced cardiomyocyte damage during I/R injury remains unknown.…”

Post-Transcriptional Regulation of Molecular Determinants during Cardiogenesis

“…Forkhead box C2 (Foxc2) participates in blood and lymphatic vessel development as well as regulating adipose cell metabolism [ 351 ]. This transcription factor is a predicted target of miR-199a-5p, a microRNA which has been implicated in cardiac remodeling regulation and ventricular hypertrophy [ 352 ]. In varicose vein tissues, the downregulation of this microRNA may promote vascular smooth muscle cells (VSMC) proliferation by upregulating Foxc2 [ 353 ].…”

Non-coding RNAs: Important participants in cardiac fibrosis

“…The roles of miR-Let7i ( 32 ), miR-1954 ( 33 ), miR-378 ( 34 ), miR-221/222 ( 35 ), miR-199a ( 36 ), miR-99b-3p ( 37 ), miR-125b ( 38 ), and miR130a ( 39 ) in cardiac fibrosis are displayed in Table 1 .…”