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Abstract
Aging is a major risk for cardiovascular diseases (CVD). Age-related disorders include oxidative stress, mitochondria dysfunction, and exacerbation of the NF-κB/NLRP3 innate immune response pathways. Some of the molecular mechanisms underlying these processes, however, remain unclear. This study tested the hypothesis that NLRP3 inflammasome plays a role in cardiac aging and melatonin is able to counteract its effects. With the aim of investigating the impact of NLRP3 inflammasome and the actions and target of melatonin in aged myocardium, we analyzed the expression of proteins implied in mitochondria dynamics, autophagy, apoptosis, Nrf2-dependent antioxidant response and mitochondria ultrastructure in heart of wild-type and NLRP3-knockout mice of 3, 12, and 24 months-old, with and without melatonin treatment. Our results showed that the absence of NLRP3 prevented age-related mitochondrial dynamic alterations in cardiac muscle with minimal effects in cardiac autophagy during aging. The deficiency of the inflammasome affected Bax/Bcl2 ratio, but not p53 or caspase 9. The Nrf2-antioxidant pathway was also unaffected by the absence of NLRP3. Furthermore, NLRP3-deficiency prevented the drop in autophagy and mice showed less mitochondrial damage than wild-type animals. Interestingly, melatonin treatment recovered mitochondrial dynamics altered by aging and had few effects on cardiac autophagy. Melatonin supplementation also had an anti-apoptotic action in addition to restoring Nrf2-antioxidant capacity and improving mitochondria ultrastructure altered by aging.
Highlights
Cardiovascular diseases (CVD) constitute the leading cause of death in the world, especially in industrialized countries [1]
We showed that aging induced a decrease in the levels of proteins involved in mitochondrial dynamics, including Mfn2, Opa1, and Drp1, in WT mice, an effect absent in NLRP3−/− mice (Figure 2A–C)
Melatonin supplementation counteracted the decline of Mfn2, Opa1, and Drp1 caused by aging in WT mice
Summary
Cardiovascular diseases (CVD) constitute the leading cause of death in the world, especially in industrialized countries [1]. Hypertension, diabetes, obesity, smoking, and physical inactivity have been identified as risk factors for these diseases [2]. Aging is by far the major risk factor for cardiac dysfunction, since its prevalence increases dramatically in aged people. Cardiac aging correlates with hemodynamic and metabolic alterations together, with changes in the structure and function of cardiovascular tissues. Aging is characterized by an increase in oxidative damage and persistent activation of innate immunity resulting in immunosenescence. This immune dysregulation results in a state of age-associated chronic inflammation termed ‘inflammaging’, which plays an important role in the onset and progression of cardiovascular diseases, in addition to other age-related disorders [9,10,11,12]
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