Table 4.

Effects of ROS scavengers and drugs recommended for diabetic subjects on myocardial ROS and oxidative stress.

Target	Model	ROS/Oxidative Stress	Cardiac Structure/Function	Author
mito-TEMPO	STZ-induced T1D mice or db/db T2D mice	↓ mitochondrial H2O2 production, intracellular ROS, protein carbonyl content, TAC ↓ gp91phox, p47phox mRNA	↓ CM hypertrophy ↓ apoptosis ↓ systolic & diastolic dysfunction	Ni [306]
Resveratrol	STZ-induced T1D mice STZ/nicotinamide-induced T1D rats Leprdb T2D mice fructose-induced T2D rat pre-diabetic ZDF rats	↓ 8OHdG, MDA, 15-F2t-IsoP ↓ SIRT1, Rab7 protein, acetylated/total histone 3, acetylated/total FOXO1 ↓ TBARS, GSSG/GSH ↑ SOD ↓ nitrite/nitrate ↓ O2•− production, NT ↑ nitrite/nitrate levels; eNOS, iNOS protein ↓ NOX activity; gp91phox, gp91phox mRNA/protein ↓ ROS, AGE, protein carbonyl content, NO content ↓ NOX activity; NOX1, NOX4 mRNA ↑ SOD activity, GSH level ↑ SIRT-1 mRNA/protein/activity ↓ mitochondrial H2O2 emission ↔ GSH/GSSG; SOD2, CAT protein	↓ cardiac dysfunction ↓ cardiac remodeling ↓ fibrosis, apoptosis ↓ apoptosis ↔ cardiac remodeling, systolic function ↓ diastolic dysfunction ↓ cardiac hypertrophy ↓ electrophysiological abnormalities ↑ NAD, NAD/NADH ratio ↓ apoptosis ↔ systolic, diastolic function ↓ cardiac fibrosis ↔ ETC subunits, ADP respiratory kinetics ↓ lipotoxicity	Wang [318] Soufi [315] Zhang [314] Bagul [317] Beaudoin [316]
Piceatannol, a natural hydroxylated analog of Resveratrol	STZ-induced T1D rats	↓ MDA, ↑ SOD activity ↑ NRF2, HO-1 mRNA	↓ systolic dysfunction ↓ fibrosis, apoptosis	Li [244]
Quercetin	high-cholesterol diet-induced T2D rats STZ-induced T1D rats	↓ 8-isoprostane, TBARS ↑ GSH/GSSG; SOD, CAT, GSH-Px activities ↑ NRF2 nuclear translocation; HO-1 mRNA ↓ 4-HNE ↑ PRX3, TRX2 protein; TRXR2 activity; ↔ PRX5 protein; ↑ SOD activity; ↔ CAT, GSH-Px activities; ↓ UCP3 protein ↑ NRF2, NRF1 mRNA	↓ diastolic dysfunction ↓ cardiac hypertrophy ↔ cardiac remodeling, systolic function ↓ CM density ↓ cardiac cholesterol content ↑ATP levels ↓ CM hypertrophy ↓ myocardial fibrosis ↑ cardiac conductivity & contractility ↓ apoptosis	Castillo [320] Arkat [181]
Taxifolin, a dihydroquercetin	STZ-induced T1D mice	↓ MDA ↑ SOD, GSH-Px, CAT activities ↓ NOX activities	↓ cardiac hypertrophy/remodeling ↓ fibrosis, apoptosis	Sun [321]
sodium selenate or omega-3/vitamin E supplementation	STZ-induced T1D rats	↔ free/total SH, nitrite	↓ cardiac dysfunction	Aydemir-Koksoy [324]
alpha-lipoic acid	STZ-induced T1D rats	↓ MDA; ↑ GSH/GSSG ↑ MnSOD activity	↓ cardiac dysfunction ↓ fibrosis	Li [325]
vitamin E	STZ-induced T1D rats	↓ 8-iso PGF2α ↓ GSSG	↓ cardiac dysfunction	Hamblin [326]
ascorbic acid, dl α-tocopherol acetate, β-carotene, N acetyl cysteine, selenium	STZ-induced T1D rats	↓ MDA ↓ XO mRNA/protein; MAO-A mRNA ↓ CAT ↓ HO-1 mRNA		Kumar [401]
coenzyme Q10	STZ-induced T1D mice	↓ 3-NT, NOX-derived O2•− production ↓ NOX2, p47phox mRNA; p22phox protein	↓ diastolic dysfunction ↓ CM hypertrophy ↓ fibrosis, apoptosis	Huynh [30], De Blasio [28]
coenzyme Q10	db/db T2D mice	↓ MDA; O2•−	↓ cardiac hypertrophy ↓ diastolic dysfunction ↓ fibrosis, apoptosis	Huynh [27]
SGLT2 inhibitor, Empagliflozin	STZ-induced T1D mice HFD-fed T2D mice ZDF obese/T2D rats db/db T2D mice KK-Ay T2D mice	↓ cytosolic & mitochondrial ROS ↓ O2•− production ↑ mtDNA content ↑ p-eNOS, NRF2, HO-1, p-p65(Ser536) protein; ↑ NRF2, HO-1 mRNA ↓ H2O2, 3-NT, GSH, and lipid peroxide; ↑ NO bioavailability ↓ p-eNOSser1177, eNOS monomer ↓ ROS ↑ SOD2; ↓ NOX4; ↔ NOX2 ↓ lipid hydroperoxide, MDA ↑ GSH-Px, SOD; ↓ NOX4 protein ↑ NRF2, HO-1 protein; nuclear NRF2	↓ LV hypertrophy ↓ diastolic dysfunction ↓ perivascular/interstitial fibrosis ↓ mitochondrial injury ↑ passive force ↓ LV hypertrophy ↓ systolic &diastolic dysfunction ↓ fibrosis, apoptosis	Lee [351] Sun [256] Kolijn [352] Xue [353] Li [355]
GLP-1RA, Exenatide	HFD-fed T2D mice & STZ-induced T1D mice [362]	↑ MnSOD, CAT protein	↓ systolic &diastolic dysfunction	Ding [362]
GLP-1RA, OHP2 & Semaglutide [354], or Exendin-4 [402]	HFD/STZ-induced T2D rats [354,402],	↓ ROS production, MDA ↓ p22phox, p40phox ↑ GSH-Px1, HO-1; ↔ SOD1 mRNA	↓ LV hypertrophy ↓ systolic & diastolic dysfunction ↓ fibrosis, apoptosis ↓ mitochondrial dysfunction, fission ↓ cardiac lipotoxicity ↑ cardiac ATP	Qian [354], Wu [402]
GLP-1RA, Exendin-4	KK-Ay or HFD-induced T2D mice [403]	↓ ROS, ↓ NOX4; ↔ NOX2 mRNA ↑ SOD, GSH-Px	↓ CM hypertrophy ↓ systolic & diastolic dysfunction ↓ fibrosis ↓ mitochondrial remodeling ↓ cardiac lipotoxicity	Monji [403]
DPP-4 inhibitor, Sitagliptin [364,365,369], Vildagliptin [365,366] or Linagliptin [367,371]	STZ-induced T1D rats HFD-fed T2D mice/rats ZDF obese/T2D rats	↓ MDA, NO, GSH content ↓ SOD, CAT activities ↓ TBARS, protein carbonylation, 3-NT, MDA, 4-HNE, ROS production ↑ CAT ↓ 3-NT; ↔ ROS, RNS ↓ iNOS	↓ cardiac hypertrophy ↓ CM degeneration ↓ fibrosis ↓ cardiac hypertrophy ↓ diastolic dysfunction ↑ HR variability ↓ cardiac fibrosis ↓ mitochondrial depolarization, swelling ↓ systolic & diastolic dysfunction ↓ ultrastructural abnormalities ↑ autophagy	Al-Rasheed [364] Apaijai [365], Nath [366], Aroor [367] Zhou [369], Aroor [371]
DPP-4 inhibitor, Alogliptin [368] or MK0626 [372]	ALX-induced T1D rabbits HFD-fed T2D mice	↓ MDA, 8-OHdG, mitochondrial ROS ↔ SOD activity ↔ 3-NT	↓ cardiac dysfunction ↓ fibrosis ↑ mitochondrial respiration ↑ mitochondrial biogenesis ↓ diastolic dysfunction ↓ fibrosis	Zhang [368] Bostick [372]
ARBSs, Candesartan [37], Valsartan [375], Azilsartan [376], and Olmesartan [238]; ACI-Is, Benazepril [37] and Ramipril [30]; renin inhibitor, Aliskiren [37,375];	STZ-induced T1D mice/rats db/db T2D mice obese OLETF T2D rats	↓ ROS; NT; ↑ GSH ↑ mitochondrial SOD activity; ↔ CAT activity; ↑ cytosolic NRF2, acetylated NRF2; ↓ Keap1 mRNA ↓ 8-OHdG, NT ↓ NT; ↑ GSH ↑ mitochondrial SOD; ↔ CAT activities ↑ cytosolic/acetylated NRF2; ↓ Keap1 mRNA	↓ LV hypertrophy ↓ systolic & diastolic dysfunction ↓ fibrosis ↓ apoptosis ↓ systolic & diastolic dysfunction ↓ cardiac hypertrophy ↓ fibrosis ↓ aconitase activity; ↔ complex I/II activities ↑ NAD+/NADH ratio	Singh [37], Thomas [375], Huynh [30] Sukumaran [376] Thorwald [238]
ARNi, LCZ696	STZ-induced T1D mice	↑ GSH, GSH/GSSG ratio	↓ cardiac hypertrophy ↓ cardiac dysfunction ↓ apoptosis & fibrosis	Ge [377]