Table 2.
The effect of melatonin in animal models of non-ischemic heart failure.
| Animal Model | Genre and Strain (Age or Weight) | Melatonin Treatment (Mode, Dose and Duration) | Effect of Melatonin and the Underlying Mechanism (↓: Decrease, ↑: Increase) | References |
|---|---|---|---|---|
| A murine model of pathological cardiac hypertrophy (induced by transverse aortic constriction) (in vivo) | Male C57BL/6 mice (20–25 g) (8–10 weeks) |
Oral, 20 mg/kg/day for 4 or 8 weeks |
Cardioprotection: ↓ pulmonary congestion, ↓ cardiac fibrosis, ↓ the deterioration of cardiac contractile function (↑ expression of the α-myosin heavy chain, ↓ expression of β-myosin heavy chain), ↓ atrial natriuretic peptide, ↑ expression of peroxisome proliferator-activated receptor-gamma coactivator-1 beta (PGC-1 β), ↓ oxidative stress | [73] |
| A rat model of hypoxic pulmonary hypertension with intermittent chronic hypoxia for 4 weeks (in vivo) | Male Sprague-Dawley rats (200–250 g) |
Intraperitoneal, 15 mg/kg/day, morning for 1 week before hypoxia and during hypoxia (4 weeks) |
Cardioprotection: ↓ right ventricular systolic pressures (RVSP), ↓ weight of the right ventricle/left ventricle plus septum (RV/LV+S) ratio, ↓ pulmonary vascular structure remodeling; ↓ proliferating cell nuclear antigen (PCNA), ↓ hypoxia-inducible factor-1alpha (HIF-1α), ↓ nuclear factor-kB (NF-kB), ↓ proliferation of primary pulmonary artery smooth muscle cells (PASMCs), ↓ phosphorylation of Akt, ↓ extracellular signal-regulated kinases1/2 (ERK1/2) |
[77] |
| Chronic intermittent hypoxia, model of a severe obstructive sleep apnea for 2 to 3 weeks (in vivo and ex vivo) | Adult Sprague-Dawley rats | Intraperitoneal, 10 mg/kg/day at 30 min before hypoxic exposure | Cardioprotection: ↓ blood pressure (BP), ↓ oxidative stress, endothelial dysfunction, and inflammation: ↑ MDA, expressions of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, pro-inflammatory mediators (TNF-α, inducible NO synthase, COX-2), ↓ cellular adhesion molecules, ↑ nitric oxide (NO˙), endothelial-dependent relaxation, endothelial NO synthase (eNOS), antioxidant enzymes (catalase (CAT), glutathione peroxidase-1 (GPx), Cu/Zn Superoxide dismutase (SOD)) | [78] |
| A rat model of isoproterenol-induced HF (in vivo) | Male Wistar rats (3 months) |
Oral, 10 mg/kg/day for 2 to 4 weeks |
Cardioprotection: ↓ cardiac fibrosis but with no effect on the right ventricle/left ventricle (LV/RV) hypertrophy; ↓ oxidative stress, insoluble and total collagen, the beta-tubulin alteration in the LV | [75] |
| Monocrotaline (MCT)- induced pulmonary hypertensive rats (ex vivo cardiac function) |
Male Long Evans rats (150–175 g) | Oral, 75 ng/L; 6 mg/kg/day or 2 or 4 weeks, preventive at 5 days before MCT for 4 weeks or curative at 2 weeks after MCT for 2 weeks |
Cardioprotection (curative and preventive): ↓ right ventricle (RV) hypertrophy, ↑ RV-function, ↓ systemic oxidative stress, ↓ cardiac interstitial fibrosis | [21] |
| Continuous light-induced hypertensive rats for 6 weeks (in vivo) | Male Wistar rats (3 months) |
10 mg/kg/day, Oral for 6 weeks |
Cardioprotection: ↓ cardiac fibrosis, oxidative stress, but with no effect on LV hypertrophy | [74] |
| A rat model of metabolic syndrome- induced cardiac injury (in vivo) | DahlS.Z-Leprfa/Leprfa (DS/obese) rats (8 weeks) |
Melatonin receptor agonist (ramelteon) at a low (0.3 mg/kg per day) or high (8 mg/kg per day) dose from 9 weeks of age, for 4 weeks | Cardioprotection: ↓ body weight gain, left ventricular fibrosis, and diastolic dysfunction, cardiac oxidative stress and inflammation, ↑ insulin signaling in visceral and subcutaneous white adipose tissue; ↓ mitochondrial uncoupling protein 1 (UCP-1), ↓ whitening of brown adipose tissue |
[34] |