Age and Chronodisruption in Mouse Heart: Effect of the NLRP3 Inflammasome and Melatonin Therapy
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AutorFernández Ortiz, Marisol; Sayed, Ramy K. A.; Román Montoya, Yolanda; Fernández Martínez, José; Ramírez Casas, Yolanda; Florido Ruiz, Javier; Rusanova Rusanova, Iryna; Escames Rosa, Germaine; Acuña Castroviejo, Darío
MelatoninClock genesChronodisruptionRhythmAgingInflammagingNLRP3 inflammasomeMouse heart
Fernández-Ortiz, M... [et al.]. Age and Chronodisruption in Mouse Heart: Effect of the NLRP3 Inflammasome and Melatonin Therapy. Int. J. Mol. Sci. 2022, 23, 6846. [https://doi.org/10.3390/ijms23126846]
PatrocinadorInstituto de Salud Carlos III (Ministerio de Economia y Competitividad, Spain) (European Regional Development Fund/European Social Fund "Investing in your future") PI13-981 PI16-00519 PI19-01372 CB16-10-00238 CB16/10/00239; Junta de Andalucia CTS-101; Spanish Government
Age and age-dependent inflammation are two main risk factors for cardiovascular diseases. Aging can also affect clock gene-related impairments such as chronodisruption and has been linked to a decline in melatonin synthesis and aggravation of the NF- B/NLRP3 innate immune response known as inflammaging. The molecular drivers of these mechanisms remain unknown. This study investigated the impact of aging and NLRP3 expression on the cardiac circadian system, and the actions of melatonin as a potential therapy to restore daily rhythms by mitigating inflammaging. We analyzed the circadian expression and rhythmicity of clock genes in heart tissue of wild-type and NLRP3-knockout mice at 3, 12, and 24 months of age, with and without melatonin treatment. Our results support that aging, NLRP3 inflammasome, and melatonin affected the cardiac clock genes expression, except for Rev-erba, which was not influenced by genotype. Aging caused small phase changes in Clock, loss of rhythmicity in Per2 and Rora, and mesor dampening of Clock, Bmal1, and Per2. NLRP3 inflammasome influenced the acrophase of Clock, Per2, and Rora. Melatonin restored the acrophase and the rhythm of clock genes affected by age or NLRP3 activation. The administration of melatonin re-established murine cardiac homeostasis by reversing age-associated chronodisruption. Altogether, these results highlight new findings about the effects aging and NLRP3 inflammasome have on clock genes in cardiac tissue, pointing to continuous melatonin as a promising therapy to placate inflammaging and restore circadian rhythm in heart muscle. Additionally, light microscopy analysis showed age-related morphological impairments in cardiomyocytes, which were less severe in mice lacking NLRP3. Melatonin supplementation preserved the structure of cardiac muscle fibers in all experimental groups.