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Cardiovascular diseases have become the leading cause of human death. Aging is an independent risk factor for cardiovascular diseases. Cardiac aging is associated with maladaptation of cellular metabolism, dysfunction (or senescence) of cardiomyocytes, a decrease in angiogenesis, and an increase in tissue scarring (fibrosis). These events eventually lead to cardiac remodeling and failure. Senescent cardiomyocytes show the hallmarks of DNA damage, endoplasmic reticulum stress, mitochondria dysfunction, contractile dysfunction, hypertrophic growth, and senescence-associated secreting phenotype (SASP). Metabolism within cardiomyocytes is essential not only to fuel the pump function of the heart but also to maintain the functional homeostasis and participate in the senescence of cardiomyocytes. The senescence of cardiomyocyte is also regulated by the non-myocytes (endothelial cells, fibroblasts, and immune cells) in the local microenvironment. On the other hand, the senescent cardiomyocytes alter their phenotypes and subsequently affect the non-myocytes in the local microenvironment and contribute to cardiac aging and pathological remodeling. In this review, we first summarized the hallmarks of the senescence of cardiomyocytes. Then, we discussed the metabolic switch within senescent cardiomyocytes and provided a discussion of the cellular communications between dysfunctional cardiomyocytes and non-myocytes in the local microenvironment. We also addressed the functions of metabolic regulators within non-myocytes in modulating myocardial microenvironment. Finally, we pointed out some interesting and important questions that are needed to be addressed by further studies. [ABSTRACT FROM AUTHOR]

Diabetes-induced tissue injuries in target organs such as the kidney, heart, eye, liver, skin, and nervous system contribute significantly to the morbidity and mortality of diabetes. However, whether the lung should be considered a diabetic target organ has been discussed for decades. Accumulating evidence shows that both pulmonary histological changes and functional abnormalities have been observed in diabetic patients, suggesting that the lung is a diabetic target organ. Mechanisms underlying diabetic lung are unclear, however, oxidative stress, systemic inflammation, and premature aging convincingly contribute to them. Circadian system and Sirtuins have been well-documented to play important roles in above mechanisms. Circadian rhythms are intrinsic mammalian biological oscillations with a period of near 24 h driven by the circadian clock system. This system plays an important role in the regulation of energy metabolism, oxidative stress, inflammation, cellular proliferation and senescence, thus impacting metabolism-related diseases, chronic airway diseases and cancers. Sirtuins, a family of adenine dinucleotide (NAD+)-dependent histone deacetylases, have been demonstrated to regulate a series of physiological processes and affect diseases such as obesity, insulin resistance, type 2 diabetes (T2DM), heart disease, cancer, and aging. In this review, we summarize recent advances in the understanding of the roles of the circadian clock and Sirtuins in regulating cellular processes and highlight the potential interactions of the circadian clock and Sirtuins in the context of diabetic lung. [ABSTRACT FROM AUTHOR]

SIRT1, a class III histone deacetylase, acts as a negative regulator for many transcription factors, and plays protective roles in inflammation and atherosclerosis. Transcription factor nuclear factor of activated T cells (NFAT) has been previously shown to play pro-inflammatory roles in endothelial cells. Inhibition of NFAT signaling may be an attractive target to regulate inflammation in atherosclerosis. However, whether NFAT transcriptional activity is suppressed by SIRT1 remains unknown. In this study, we found that SIRT1 suppressed NFAT-mediated transcriptional activity. SIRT1 interacted with NFAT, and the NHR and RHR domains of NFAT mediated the interaction with SIRT1. Moreover, we found that SIRT1 primarily deacetylated NFATc3. Adenoviral over-expression of SIRT1 suppressed PMA and calcium ionophore Ionomycin (PMA/Io)-induced COX-2 expression in human umbilical vein endothelial cells (HUVECs), while SIRT1 RNAi reversed the effects in HUVECs. Moreover, inhibition of COX-2 expression by SIRT1 in PMA/Io-treated HUVECs was largely abrogated by inhibiting NFAT activation. Furthermore, SIRT1 inhibited NFAT-induced COX-2 promoter activity, and reduced NFAT binding to the COX-2 promoter in PMA/Io-treated HUVECs. These results suggest that suppression of NFAT transcriptional activity is involved in SIRT1-mediated inhibition of COX-2 expression induced by PMA/Io, and that the negative regulatory mechanisms of NFAT by SIRT1 may contribute to its anti-inflammatory effects in atherosclerosis. [ABSTRACT FROM AUTHOR]

Angiotensin II (AngII) induces the development of vascular hypertrophy and hypertension. We have shown previously that overexpression of class III deacetylase SIRT1 inhibits AngII-induced hypertrophy in vascular smooth muscle cells (VSMCs). However, the direct role of SIRT1 in VSMCs in response to AngII infusion in vivo remains unclear. Here, we found that the expression and activity of SIRT1 in mouse aortas was decreased significantly by AngII infusion. VSMC-specific SIRT1 transgene (SV-Tg) prevented the increase in systolic blood pressure (SBP) caused by AngII infusion without affecting heart function in mice. SIRT1 overexpression alleviated vascular remodeling in mouse thoracic and renal aortas induced by AngII infusion, and significantly inhibited reactive oxygen species (ROS) generation, vascular inflammation, and collagen synthesis in arterial walls. Reduced expression of transforming growth factor-β 1 (TGF-β1) was also observed in the aortas of AngII-infused SV-Tg mice. Moreover, SIRT1 overexpression decreased AngII-increased binding of nuclear factor-κB on its specific binding sites on TGF-β1 promoter. Taken together, these data demonstrate that SIRT1 overexpression in VSMCs reduces SBP and inhibits AngII-induced vascular remodeling in mice. The inhibition of vascular remodeling contributes, at least in part, to the antihypertensive effect of SIRT1. Key message: [ABSTRACT FROM AUTHOR]