Table 1 Evaluating miRNAs as a treatment approach in diabetic cardiomyopathy

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