Table 2 Evaluating lncRNAs as a treatment approach in diabetic cardiomyopathy

Upregulated lncRNAs

[141, 142]

↑ANRIL

–

CDH5

HBEGF

Inflammation Oxidative stress Apoptosis Fibrosis

STZ-induced diabetes model*

In vitro, rats

(Wistar rats, ANRILsiRNA group intraperitoneal injections of ANRIL siRNA or siRNA-negative control (NC) group

*Diabetes was induced by intraperitoneal injection of STZ at 40 mg/kg per mouse. Mice with hyperglycemia (3 h FBG levels ≥ 16.7 mmol/l for 3 days were considered as having diabetes

ANRIL is upregulated in rat diabetic model. ANRIL siRNA treatment revealed improvement in cardiac function, LVEF, LVFS were elevated and LVEDD, LVPWD were decreased among diabetic rats. Diminishing ANRIL expression decreased myocardial inflammation as TNFα, IL‐6, IL‐1β levels were reduced, suppressed fibrosis via diminishing Col1, Col2 and alleviated apoptosis through downregulating caspase-3, Bax and upregulating Bcl-2, also diminished oxidative stress via decreasing ROS, and MDA.

[133]

↑Kcnq1ot1

miR-214-3p

ADIPOR1 Kcnq1

Inflammation

Pyroptosis

T1DM STZ-induced diabetes model*

In vivo, human blood serum, mice

In vitro, human AC16 cells and mice cardiomyocytes

(C57BL/6 mice and ventricular cardiomyocytes (AC16 cell line) and primary cardiomyocytes treated with 50 mmol/l glucose (HG) conditions were used. Cells were transfected with small interfering RNA (siRNA) against Kcnq1ot1 (si-Kcnq1ot1), miR-214-3p mimics (miR-214-3p), the anti-miRNA oligonucleotide of miR-214-3p (AMO-214-3p) or negative control (si-NC, NC, AMO-NC) using X-treme GENE siRNA Transfection Reagent

*Diabetes was induced by an intraperitoneal injection of STZ 50 mg/kg/day for 5 days. Mice with glucose levels ≥ 16.7 mmol/l were considered as having diabetes

Kcnq1ot1 is overexpressed in serum of diabetic patients and in HG-induced cardiomyocytes. Silencing Kcnq1ot1 inhibits cardiomyocytes pyroptosis by blocking CASP-1 via miR-214-3p

[132, 133]

↑Kcnq1ot1

miR-214-3p

ADIPOR1 Kcnq1

Inflammation Pyroptosis Fibrosis

STZ-induced diabetes model*

In vivo, human blood serum

In vivo, in vitro, mice

(C57BL/6 mice, cardiomyocytes incubated with 30 mmol/l glucose (HG) for 24 h were used), Cells were transfected with small interfering RNA (siRNA) against Kcnq1ot1 (si-Kcnq1ot1), miR-214-3p mimics (miR-214-3p), the anti-miRNA oligonucleotide of miR-214-3p (AMO-214-3p) or negative control (si-NC, NC, AMO-NC) using X-treme GENE siRNA Transfection Reagent

*Diabetes was induced by an intraperitoneal injection of STZ 50 mg/kg/day for 5 days. After 72 h, mice with blood glucose of > 16.7 mmol/l were considered as having diabetes

Kcnq1ot1 is increased in LV tissue of diabetic mice and corresponds with myocardial dysfunction progression. Knockdown of Kcnq1ot1 by a lentivirus-shRNA resulted in enhanced cardiac function. Kcnq1ot1 silencing stimulated gasdermin D cleavage and IL-1β expression and therefore suppressed TGF-β1/smads pathway via miR-214-3p and CASP-1 in HG-induced CFs

[124]

↑MALAT1

miR-26a

HMGB1

Apoptosis

In vitro, human adult ventricular cardiomyocytes (AC16 cell line)*

*AC16 cells were treated with 300 ĶM palmitic acid to induce myocardial lipotoxic injury transfected with siRNA (negati, miR-26a mimics, NC mimics, miR-26a inhibitor, NC inhibitor, and TNF-α-specific siRNA (si-TNF-α)

MALAT1 overexpression is promoted by SFAs. MALAT1 directly binds to miR-26a. Silencing of MALAT1 diminished cardiac inflammatory injury via modulating miR-26a/HMGB1/TLR4/NF-κB signaling pathway, suggesting MALAT1 capability to regulate inflammatory processes

[140]

↑MALAT1

–

SAA3

Inflammation

STZ-induced diabetes model*

In vivo, in vitro, mice kidney tissues

(HUVECs incubated in 25 mM D-Glucose (HG) condition)

*Diabetes was induced by an intraperitoneal injection of STZ (70 mg/kg of mice) × 3 on alternate days

Hyperglycemia stimulates MALAT1 expression and SAA3 in HUVECs. Silencing of MALAT1 and SAA3 expression alleviated the inflammation process via the downregulation of IL-6 and TNFa levels. MALAT1 is upregulated in the kidneys of diabetic mice. MALAT1 directly targets the SAA3 gene, which is a key regulator of inflammatory cascade

[128]

↑NONRATT007560.2

miR-7a-1-3

miR-92a-2-5p

miR-208a-5p

miR-208b-5p

miR-3065-5p

miR-3575

–

Oxidative stress Apoptosis

HG- induced diabetes model*

In vitro, Sprague

.Dawley rats, cardiomyocytes incubated with 5 mmol/l D-glucose (NG) or 33 mmol/l D-Glucose (HG)

HG stimulated cardiomyocytes demonstrated elevated levels of NONRATT007560.2 and induced apoptosis

Silencing of NONRATT007560.2 suppressed apoptosis and oxidative stress via decreasing ROS in rat cardiomyocytes

t

[127]

↓H19

miR-675

VDAC1

Inflammation Apoptosis

STZ-induced diabetes model*

In vitro, primary neonatal rats cardiomyocytes transfected with miR-30d mimic, and negative control (NC) using X-treme Gene siRNA Transfection Reagent

in silico,

in vivo, Wistar rats,

*Diabetic rats were injected intraperitoneally with 35 mg/kg/d of STZ for 3 days. Fasting blood glucose levels were measured 72 h after STZ injection and diabetes was considered successfully established in rats with blood glucose levels > 16.7 mmol/l

HG exposure reduced H19 expression. Overexpression of H19 improved LV function in diabetic rats by diminishing oxidative stress, inflammation and apoptosis. H19 impacts myocardial apoptosis in DCM. H19 decreased myocardial apoptosis via miR-675 which directly targeted apoptosis-related VDAC1 gene

[125]

↓HOTAIR

miR-34a

SIRT

Inflammation Oxidative stress Apoptosis Fibrosis

T1DM STZ-induced diabetes model*

In vivo,mice

In vitro, mice, rats cardiomyocytes

(Male C57/B6 mice were given a single injection of adeno-associated virus (AAV) 2-HOTAIR)

H9c2 cells were exposed to high glucose and infected with shHOTAIR for 4 h

Mice cardiomyocytes were exposed to a HG concentration (33 mM glucose) and transfected with miR-34a mimics, antagomiR-34a, and their control were synthesized

*Diabetes was induced by intraperitoneal injection of STZ at 50 mg/kg per mouse for 5 consecutive days. Mice with hyperglycemia (3 h FBG levels ≥ 250 mg/dl) were considered as having diabetes

Decreased HOTAIR stimulated HG-induced oxidative stress, inflammation, apoptosis in STZ-treated mice. HOTAIR overexpression downregulates levels of fibrotic markers