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Table 1 Evaluating miRNAs as a treatment approach in diabetic cardiomyopathy

From: MicroRNAs and long non-coding RNAs in the pathophysiological processes of diabetic cardiomyopathy: emerging biomarkers and potential therapeutics

Refs. miRNA
Down- or up-regulation
Regulated genes Pathophysiological mechanism Species, material, method Conclusion
Upregulated miRNAs in DCM
[44] ↑miR-19b
↑miR-27a
↑miR-34a
↑miR-125b
↑miR-146a
↑miR-155
↑miR-210
↑miR-221
P27/
mTOR
calcineurin/NFAT
Oxidative stress
Hypertrophy
Apoptosis
STZ-induced diabetes model*
In vivo,
(C57/B6 mice were used)
*Diabetes was induced by a single high dose of STZ, 180 mg/kg, via intraperitoneal injection. Hyperglycemia was defined as 3 random blood glucose levels > 13.9 mmol/l
MiRNAs regulating redox signalling pathways (miR-221, miR-146a, miR-34a, miR-210, miR-19b, miR-125b, miR-27a, miR-155) were persistently dysregulated after normalization of blood glucose levels
MiR-221 modulates cardiac hypertrophy via P27/mTOR, calcineurin/NFAT signaling pathway
[37] miR-21 PPARα,
Nrf2
Oxidative stress
Inflammation Apoptosis
STZ-induced diabetes model*
In vivo, in vitro, mice, rats
(C57/B6J mice with generated LAZ3 knock down model by retro-orbital venous injection of AAV9-shLAZ3, NRCM cells transfected with adenovirus (Ad-) to overexpress LAZ3 were used), and were infected with Ad-LAZ3 and co-cultured with miR-21 mimic, miR-361 mimic or miR-155 mimic
*Diabetic animal model was established by intraperitoneal STZ injection at a dose of 50 mg/kg for 5 consecutive days. One week after the final STZ injection, fasting blood glucose was measured. Diabetes was defined as FBG ≥ 16.6 mmol/L
LAZ3 is decreased in DCM mouse hearts and rats cardiomyocytes. LAZ3 inhibition enhanced miR-21, miR-155, miR-361 expression levels. LAZ3 modulates the PPARα/Nrf2 pathway while downregulating miR-21. Knockdown of LAZ3 induces a severe inflammation, oxidative stress and apoptosis in rat cardiomyocytes. Contrarily, the increase of LAZ3 inhibits HG provoked myocardial injury
[38] ↑miR-30d FOXO3 Inflammation
Pyroptosis
Apoptosis
STZ-induced diabetes model*
In vivo, in vitro,
(Wistar rats and NRCM cells were used and were transfected with miR-30d mimics (AMO-mir-30d) and NC miRNA (AMO-NC) using X-treme GENE siRNA Transfection Reagent)
*Diabetic Wistar rats were injected intraperitoneally with 35 mg/kg/d of STZ for 3 days. Diabetes was defined as glucose level ≥ 16.7 mM
Enhanced miR-30d inhibited FOXO3 resulting in decreased ARC and therefore increased CASP-1, and pro-inflammatory cytokines IL-1β, IL-18 levels confirming its role in DCM progression
[102] ↑miR-30d KLF9/VEGFA Autophagy STZ-induced diabetes model*
in vivo, rats
Sprague Dawley rats were fed with a high-fat diet during 10 week and injected with STZ 30 mg/kg/d for 5 consecutive days. Diabetes was defined as at least two glucose levels ≥ 16.7 mmol/L or one fasting glucose ≥ 8.0 mmol/L
SGLT-2 inhibitors can regulate the autophagy level in diabetic rats through the miR-30d/KLF9/VEGFA pathway, thereby improving cardiac function
[60] ↑miR-150-5p Smad7 Fibrosis
Inflammation
HG- induced diabetes model*
In vitro, rats cardiac fibroblasts
*Neonatal cardiac fibroblasts were treated with HG (30 mM, 50 mM) DMEM in the presence of the TGF-β1 inhibitor or NF-kB inhibitor for 24 h and were transfected with miR-15-5p mimics and miR-15-5p inhibitor
(AMO-150-5p)
inhibitor using
X-treme GENE siRNA Transfection
Reagent
Smad7 is the direct target of miR-150-5p
Inhibition of miR-150-5p could prevent NF-kB induced inflammation and TGF-β1/Smad-triggered cardiac fibrosis by targeting Smad7
[50, 162] ↑miR-155 SHIP-1
SOCS1
BCL6
Inflammation
Apoptosis
Fibrosis
STZ-induced diabetes model*
In vivo, in vitro
(C57/BL6 mice, RAW 264.7 cells were transfected with miR-155 mimics and miR-155 inhibitors)
*C57/BL6 mice were injected intraperitoneally with a low dose of STZ (50 mg/day/kg) for 5 consecutive days, hyperglycemia was defined as glucose level > 22 mmol/L after 2 weeks
Overexpression of miR-155 caused disbalance between proinflammatory (M1) and anti-inflammatory (M2) macrophages causing impaired cardiac hemostasis
MiR-155 promoted M1 polarization and therefore enhanced inflammation
AuNP-mediated anti-miR-155 delivery stimulated M2 polarization, therefore diminished cells apoptosis, inflammation, fibrosis and enhanced cardiac function in OVX mice
[104] ↑miR-195 BCL2
SIRT
Oxidative stress
Apoptosis
Hypertrophy
T1DM STZ-induced diabetes model*
T2DM model by using db/db mice
In vitro, in vivo,
(C57BL/6 mice, db/db mice cardiomyocytes and ECs were infected with adenoviral vectors containing miR-195 (Ad-miR-195) or β-gal as a control
*Diabetes was induced in mice by consecutive peritoneal injections of STZ 50 mg/kg/d for 5 days. Diabetes was defined as glucose level ≥ 15 mmol/l at 72 h after STZ injection, to silence miR-195 expression in hearts, we used antimiR-195 miR construct (miRZip-195)
MiR-195 expression was increased and levels of its target proteins BCL2 and SIRT1 were decreased in STZ-induced type 1 and db/db type 2 diabetic mouse hearts. In vivo inhibition of miR-195 led to the improved coronary blood flow, increased both BCL2 and SIRT1 expression and resulted in the downregulation of TNFα, IL-1β and CASP-3 activity
[93] ↑miR-503 Nrf2 Oxidative stress
Apoptosis
STZ-induced diabetes model*
In vitro, in vivo,
(Male Wistar rats, rats primary cardiomyocytes, HEK293T transfected with miR-503 mimics, NC mimics)
*Rats in the DM group were fed with a high-fat diet per day. 30 mg/kg/d of STZ was injected intraperitoneally for 3 consecutive days. Diabetes was defined as glucose level ≥ 16.7 mM
Increased levels of miR-503 impact DCM progression. Decreased miR-503 is involved in decreasing DCM progression via CPDT which is activating Nrf2/ARE pathway and Nrf2 is target gene for miR-503
Downregulated miRNAs inDCM
[45] ↓miR-1 Junctin Oxidative stress T1DM STZ-induced diabetes model*
In vivo, in vitro,
(Wistar rats and mice C2C12 cells were used)
*Diabetes was induced by single intraperitoneal injection of STZ (50 mg/kg)
MiR-1 directly targets junctin and suppresses its expression. Decreased levels of miR-1 in HG-conditions result in increased expression of junctin
Overexpression of junctin induced cardiac hypertrophy and arrhythmia via adaptive changes in Ca2 + handling
[44] ↓miR-1 Fibulin-1 Oxidative stress
Hypertrophy
Fibrosis
STZ-induced diabetes model*
In vivo,
(C57/B6 mice were used)
*Diabetes was induced by a single high dose of STZ, 180 mg/kg, via intraperitoneal injection. Hyperglycemia was defined as 3 random blood glucose levels > 13.9 mmol/l
MiR-1 replacement treatment is suggested to play a crucial role in cardiac hypertrophy and fibrosis by targeting Fibulin-1
[103] ↓miR-9 ELAVL1 CASP-1 Inflammation
Pyroptosis
In vitro, human
(Human diabetic heart tissue obtained from failing hearts at the time of transplantation, diabetic human cultured cardiomyocytes were co-transfected with control or miR-9 mimic or miR-9 inhibitor
H9C2
Raw 264.7
Expression of miR-9 is downregulated in human diabetic failing heart. Upregulation of miR-9 reduces ELAVL1, CASP-1 and IL-1β expression in human cardiomyocytes
[121] ↓miR-21 Gelsolin Oxidative stress
Hypertrophy
In vivo, in vitro,
(C57BL/Ks mice transfected with rAAV-tnt-GFP,
rAAV-tnt-miR-21, and rAAV-tnt-miR-21-TUD;
H9c2, HEK293 cells, HL-1 cardiac muscle cell line from AT-1 mouse and human cardiomyocytes were used)
MiR-21 is downregulated in cardiomyocytes in diabetic mice model
MiR-21 directly targeted gelsolin and inhibited the gelsolin pathway
Mimic miR-21 treatment reduced myocardial hypertrophy in diastolic dysfunction db/db mice by diminishing ROS levels and increasing eNOS forced release in db/db mice
[94] ↓miR-22 SIRT1 Oxidative stress,
Apoptosis
T1DM STZ-induced diabetes model*
In vivo, in vitro,
mice
(C57BL/6 mice, embryonic cardiac myoblast cell line (H9c2 cells)—cultured in high glucose conditions were used)
*Diabetes was induced in mice by consecutive peritoneal injections of STZ 50 mg/kg/d for 5 days. Diabetes was defined as glucose level ≥ 16.6 mmol/l
MiR-22 was found downregulated in the hearts of diabetic mice. Increased miR-22 expression enhanced cardiac function in DCM by increasing SOD levels and decreasing ROS, MDA levels
Additionally, miR-22 is able to block Bax/Bcl-2, cl-CASP-3/CASP-3 and cl-CASP-9/CASP-9 in HG-treated H9c2 cells
[80] ↓miR-30c PGC-1β Oxidative stress
Apoptosis
T1DM STZ-induced diabetes model*
In vivo, in vitro,
(db/db C57BL/Ks mice, H9c2 cells, HEK293T primary NRC)
Db/db mice had single tail vein injection of the
rAAV-miR-30c or rAAV-anti-miR-30c randomly, H9c2 cells were first transfected with PGC-1β siRNA or miR-30c, and then transfected with pTK-PPREx3-Luc plasmid. HEK293T cells were co-transfected with appropriate pMIR construct, pRL-TK plasmid with miR-30c mimics or negative controls
In the diabetic mouse model, miR-30c levels were downregulated. Upregulation of miR-30c decreased PGC-1β expression and therefore lipotoxicity and cardiac dysfunction suggesting its cardioprotective role
PGC-1β knockdown inhibited PPRAα transcriptional activity in diabetic mouse hearts
[86] ↓MiR-30c Cdc42, Pak1 Cardiomyocytehypertrophy STZ-induced diabetes model*
in vitro, in vivo, rats, human cardiac tissue
*Diabetes in Wistar rats was induced by two injections of STZ 30 mg/kg/d a week apart, preceded by 4 weeks of high-fat-diet
Downregulation of miR-30c mediates prohypertrophic effects of hyperglycemia in DCM by upregulation of Cdc42 and Pak1 genes
[87] ↓MiR-30c p53, p21 Hypertrophy, apoptosis STZ-induced diabetes model*
in vitro, in vivo, rats, human cardiac tissue
*Wistar rats were fed high-fat-diet for 4 weeks, followed by two injections of STZ 30 mg/kg/d, a week apart
Dysregulation of miR-30c and miR-181a may be involved in upregulation of the p53–p21 pathway in DCM
[88] ↓MiR-30c BECN1 Autophagy in vitro, in vivo, human plasma, mice, rat cardiomyocytes
Plasma obtained from healthy controls (n = 28), DM patients (n = 26), patients with chronic HF (n = 16), and patients with both DM and chronic HF (n = 15)
Diabetic cardiomyopathy db/db mice and non-diabetic control C57BL/Ks mice
Downregulation of miR-30c and subsequent activation of BECN1 promotes autophagy, contributing to the pathogenesis of DCM
[51] ↓miR-126 ADAM9 Inflammation
Apoptosis
In vitro,
human, mice
(Human heart tissue obtained from failing human hearts at the time of transplantation, mouse bone marrow derived macrophages (BMM) from
non-diabetic and diabetic (db/db) mice, RAW 264.7 cells cultured in hyperglycemia (HG; 35 mM) conditions, BMM diabetic (db/db) cells were used)
Inhibition of miR-126 attenuate efferocytosis via upregulating ADAM9
Increased ADAM9 causes proteolytic cleavage of MerTK and inactive form of sMER
Downregulation of MerTK phosphorylation diminished efferocytosis of apoptotic cells and reduced inflammation
[112] ↓MiR-133a SGK1, IGF1R Hypertrophy STZ-induced diabetes model*
in vitro, in vivo, mice, neonatal rat myocytes
* C57BL/6 J mice injected STZ 50 mg/kg/d 3 consecutive days. Diabetes was defined as blood glucose level > 20 mmol/L on two consecutive days
Mir-133a mediates novel glucose-induced mechanism regulating gene expression and cardiomyocyte hypertrophy in diabetes
[113] ↓MiR-133a ERK1/2, SMAD-2 Fibrosis STZ-induced diabetes model*
in vivo, mice
Four types of animals: wild-type non-transgenic, non-transgenic with 2 months of (STZ)-induced diabetes, non-diabetic cardiac miR-133a transgenic and cardiac miR-133a transgenic with STZ-induced diabetes
* mice were injected by STZ 65 mg/kg i.p for three consecutive days
In diabetic mice with cardiac-specific miR-133aa overexpression, cardiac fibrosis was significantly decreased. Furthermore, cardiac miR-133a overexpression prevented ERK1/2 and SMAD-2 phosphorylation. MiR-133a could be a potential therapeutic target for diabetes-induced cardiac fibrosis and related cardiac dysfunction
[66] ↓miR-142-3p Smad Fibrosis in vitro,
Primary human aortic endothelial cells (HAECs) were used
miR-142-3p could attenuate high glucose induced endothelial-to-mesenchymal transition in HAECs, the mechanism of which may at least partly involve blocking TGF-β1/Smad signaling pathway. This might provide a potential therapeutic target for DCM in the future
[34] ↓miR-144 Nrf2 Oxidative stress,
Apoptosis
T1DM STZ-induced diabetes model*
In vivo, in vitro,
(C57BL/6 mice and mice cardiomyocytes incubated with 33 mmol/l glucose (HG) for 48 h were used and were transfected with miR-144 mimic or with miR-144 inhibitor)
*C57/BL6 mice were injected intraperitoneally with STZ solution (150 mg/kg). Diabetes was defined as glucose level ≥ 16.7 mM
MiR-144 level was lower in heart tissues of STZ-induced diabetic mice and in cardiomyocytes cultured in HG conditions. However, further inhibition of miR-144 demonstrated both diminished oxidative stress and apoptosis resulting in enhanced myocardial function via increased Nrf2 which is the main modulator of cellular reaction to oxidative stress
[71] ↓miR-146a IRAK, TRAF6
NFKB
IL6
TNFA
IL1B
Inflammation STZ-induced diabetes model*
In vitro, human, HCMECs**
in vivo, mice, primary mouse cardiac endothelial cells (MHECs)
*C57BL/6 X CBA/J transgenic mice with miR-146a overexpression,
Diabetic animals were induced by 5 intraperitoneal injections of STZ (50 mg/kg) on consecutive days
**Human cardiac microvascular endothelial cells (HCMECs) were incubated with 25 mM glucose (HG) for 48 h. HCMECs were transfected with miRIDIAN miR-146a mimic or antagomir (20 nmol/L) using the transfection reagent Lipofectamine2000
Decreased miR-146a expression resulted in increased IL-6, TNFα, IL-1β, MCP-1, NF-κB, Col1α1, Col4α1 through TRAF/IRAK/ NF-κB pathway and the overexpression of miR-146a reversed this effect suggesting its cardioprotective role
[59] ↓miR-203 PIK3CA
PI3KT/Akt
Oxidative stress
Hypertrophy
Fibrosis
Apoptosis
STZ-induced diabetes model*
In vivo (C57BL/6 mice)
*C57/BL6 mice were injected intraperitoneally with STZ solution (50 mg/kg) for 5 consecutive days
PIK3CA is involved in progression of DCM PIK3CA is directly targeted via miR-203 and impacts PI3K/Akt signaling pathway
Increased miR-203 expression and inhibition of PI3K/Akt pathway decreased cardiac fibrosis in diabetic mice model
[43] ↓miR-373 MEF2C Hypertrophy STZ-induced diabetes model*
in vitro, in vivo, mice, neonatal rat myocytes
* diabetes in C57/BL6 male mice was induced by a single injection of STZ, 150 mg/kg. Diabetes was defined as blood glucose level ≥ 18.6 mmol/L on two consecutive days
Overexpression of miR-373 decreased the cell size, and reduced the level of its target gene MEF2C. miR-373 expression was regulated by p38, the member of MAPK subgroup which were specifically upregulated in cardiomyocyte hypertrophy during hyperglycemia
  1. ↑ / ↓indicates the up/down regulation of the miRNAs determined in the HG conditions / diabetic heart model
  2. Ad adenovirus, ADAM9 ADAM metallopeptidase domain 9, AP-1 activator protein 1, ARC activity regulated cytoskeleton associated protein, ARE antioxidant response element, AT-1 angiotensin II receptor type 1, AuNP gold nanoparticle, Bax Bcl-2-associated X protein, Bcl2 B-cell lymphoma 2, BCL6 BCL6 transcription repressor, BMM bone marrow-derived macrophages, Ca calcium, CASP-1 caspase 1, c-Fos Fos proto-oncogene, CFs cardiac fibroblasts, Col1α1 collagen Type I alpha 1, Col4α1 collagen type IV alpha 1, CPDT 5,6-dihydrocyclopenta-1,2-dithiole-3-thione, db/db diabetic, DCM diabetic cardiomyopathy, ECs endothelial cells, ELAVL1 ELAV like protein 1, eNOS endothelial NOS, FBG fasting blood glucose, FOXO3 Forkhead box O3, GFP green fluorescent protein, hCMECs human cerebral microvascular endothelial cells, HEK293T human embryonic kidney cells, HF heart failure, HG high-glucose, ICM ischemic cardiomyopathy, IL interleukin, IRAK interleukin-1 receptor-associated kinase, kg kilogram, L litre, LAZ3 lymphoma-associated zinc finger 3, LV left ventricle, MCP-1 monocyte chemoattractant protein-1, MDA malondialdehyde, MerTK MER proto-oncogene, tyrosine kinase, MHECs mouse heart endothelial cells, mg milligram, miRNA, miR microRNA, mM millimolar, mmol millimole, MMP-9 matrix metallopeptidase 9, mTOR mammalian target of rapamycin, NC negative control, NFAT nuclear factor of activated T-cells, NF-κB nuclear factor kappa-light-chain-enhancer of activated B cells, NRCM neonatal rat cardiomyocytes, Nrf2 nuclear factor erythroid 2-related factor 2, OVX ovariectomized, pcDNA p-complementary DNA, PGC-1β peroxisome proliferator-activated receptor gamma coactivator 1-alpha, PI3KT phosphoinositide 3-kinase, PI3K/Akt phosphoinositide 3-kinase and protein kinase B, PIK3CA phosphoinositide 3-kinase catalytic subunit alpha, PPARα peroxisome proliferator-activated receptor-alpha, pRL-TK thymidine kinase promoter-Renilla luciferase reporter plasmid, ROS reactive oxygen species, SHIP-1 phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase 1, siRNA small interfering RNA, SOCS1 the suppressor of cytokine signaling–1, SOD superoxide dismutase, Sirt Sirtuin, Smad7 SMAD family member 7, sMER soluble MER, STZ streptozocin, T1DM Type 1 diabetes mellitus, TGF-β1 transforming growth factor β1, TNFα tumor necrosis factor-alpha, TRAF TNF receptor associated factor