MiR‐144 protects the heart from hyperglycemia‐induced injury by regulating mitochondrial biogenesis and cardiomyocyte apoptosis

Abstract

contributed equally to this work.Abbreviations: AMPK, adenosine monophosphate-activated protein kinase; ATP, adenosine triphosphate; A, atrial contraction; BSA, bovine serum albumin; CAD, coronary artery disease; DCM, diabetic cardiomyopathy; DMEM, Dulbecco's modified Eagle's medium; E, peak filling rates of the early filling phase; e', early diastolic lengthening mitral valve flow velocity; EF, ejection fraction; eNOs, endothelial NO synthase; FBS, fetal bovine serum; FS, left ventricular fractional shortening; Gated-MPI, Gated-myocardial perfusion imaging; HG, high glucose; LVDD, left ventricle diastolic dysfunction; LVIDd, left ventricular internal dimension-diastole; LVIDs, left ventricular internal dimension-systole; LV mass, left ventricular mass; miRNA, microRNA; mtDNA, mitochondrial DNA; NC, negative control; Nox, nicotinamide adenine dinucleotide phosphate oxidase; NRF1, nuclear respiratory factor 1; OXPHOS, oxidative phosphorylation; PAK, p21-activated protein kinase; PBD, p21-binding domain; PFA, paraformaldehyde; PGC-1α, peroxisome proliferator-activated receptor γ coactivator 1α; qRT-PCR, Quantitative real-time polymerase chain reactions; ROC, receiver-operator characteristic; ROS, reactive oxygen species; SIRT1, silent information regulator 1; SPF, specific pathogen-free; STZ, streptozotocin; TCA, , tricarboxylic acid; T2DM, type 2 diabetes; TFAM, mitochondrial transcription factor A; TEM, transmission electron microscope; TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP in situ nick end labeling; VADT, veterans affairs diabetes trial; WGA, wheat germ agglutinin. AbstractSeveral lines of evidence have revealed the potential of microRNAs (miRNAs, miRs) as biomarkers for detecting diabetic cardiomyopathy, although their functions in hyperglycemic cardiac dysfunction are still lacking. In this study, mitochondrial biogenesis was markedly impaired induced by high glucose (HG), as evidenced by dysregulated mitochondrial structure, reduced mitochondrial DNA contents, and biogenesis-related mRNA levels, accompanied by increased cell apoptosis. MiR-144 was identified to be decreased in HG-induced cardiomyocytes and in streptozotocin (STZ)-challenged heart samples. Forced miR-144 expression enhanced mitochondrial biogenesis and suppressed cell apoptosis, while miR-144 inhibition exhibited the opposite results. Rac-1 was identified as a target gene of miR-144. Decreased Rac-1 levels activated AMPK phosphorylation and PGC-1α deacetylation, leading to increased mitochondrial biogenesis and reduced cell apoptosis. Importantly, the systemic neutralization of miR-144 attenuated mitochondrial disorder and ventricular dysfunction following STZ treatment. Additionally, plasma miR-144 decreased markedly in diabetic patients with cardiac dysfunction. The receiver-operator characteristic curve showed that plasma miR-144 could specifically predict diabetic patients developing cardiac dysfunction. In conclusion, this study provides strong 2174 |

Irisin ameliorates high glucose‐induced cardiomyocytes injury via AMPK/mTOR signal pathway

“…CMs injury induced by HG is a major contributor to the development of diabetic cardiomyopathy (Tao, Huang, Xu, Yang, & Hua, 2019; H. L. Zhao et al, 2018). Irisin, the extracellular domain of FNDC5, recognized as a myokine secreted from skeletal muscle, played a cardioprotective role in cardiac injury (Ouyang et al, 2020).…”

Mitochondria and metabolic transitions in cardiomyocytes: lessons from development for stem cell-derived cardiomyocytes

“…In addition, elevated glucose levels inhibit AMPK signaling which can adversely affect mitochondrial biogenesis and dynamics; activation of AMPK with berberine can reverse hyperglycemia-induced effects, leading to enhanced mitochondrial function by stimulating biogenesis and promoting mitophagy of dysfunctional mitochondria [158]. MiR-144 is decreased in hyperglycemic conditions, but overexpression of miR-144 can promote mitochondrial biogenesis and reduce apoptosis via AMPK phosphorylation and PGC1α deacetylation [159].…”

MicroRNAs Regulating Mitochondrial Function in Cardiac Diseases

“…MiR-27b and miR-25 inhibit mitochondrial biogenesis by downregulating the expression of forkhead box J3 (Foxj3) and P53, respectively (Wang et al, 2016;Shen et al, 2016). Additionally, miR-144 and miR-142-3p promote mitochondrial biogenesis by targeting the rac family small gtpase 1(Rac1) to activate PGC-1α (Tao et al, 2020;Xia et al, 2020).…”

“…MiR-141 was upregulated in the hearts of STZ-induced FVB mice, which inhibited the translation of mitochondrion phosphate carrier (Slc25a3) without affecting the transcription level, resulting in decreased ATP synthetase activity (Baseler et al, 2012). Recently, the overexpression of miR-144 was found to specifically inhibit Rac-1, regulating the AMPK-PGC-1 α signal, enhancing mitochondrial biogenesis, upregulating the copy number of mtDNA, and restoring the mitochondrial membrane potential, which improved the DCM induced by HG and STZ both in vitro and in vivo (Tao et al, 2020).…”