Virag JA, Dries JL, Easton PR, Friesland AM, DeAntonio JH, Chintalgattu V, Cozzi E, Lehmann BD, Ding JM, Lust RM. Attenuation of myocardial injury in mice with functional deletion of the circadian rhythm gene mPer2.

Low-avidity autoreactive CD8 T cells (CTLs) escape from thymic negative selection, and peripheral tolerance mechanisms are essential for their regulation. We report the role of proinsulin (PI) expression on the development and activation of insulin-specific CTLs in the NOD mouse model of type 1 diabetes. We studied insulin B-chain-specific CTL from different T-cell receptor transgenic mice (G9Cα) expressing normal PI1 and PI2 or altered PI expression levels. In the absence of PI2 (Ins2), CTL in pancreatic lymph nodes (PLNs) were more activated, and male G9Cα mice developed T1D. Furthermore, when the insulin-specific CTLs developed in transgenic mice lacking their specific PI epitope, the CTLs demonstrated increased cytotoxicity and proliferation in vitro and in vivo in the PLNs after adoptive transfer into NOD recipients. Dendritic cell-stimulated proliferation of insulin-specific T cells was reduced in the presence of lymph node stromal cells (LNSCs) from NOD mice but not from mice lacking the PI epitope. Our study shows that LNSCs regulate CTL activation and suggests that exposure to PI in the periphery is very important in maintenance of tolerance of autoreactive T cells. This is relevant for human type 1 diabetes and has implications for the use of antigen-specific therapy in tolerance induction.

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Variations in circadian patterns are evident in the incidence of cardiovascular disease and derangements in normal circadian patterns are demonstrated to precipitate the onset of chronic diseases. “Clock genes” such as Per-1 and -2, Cry-1 and -2, and clock/bmal , are found in all peripheral tissues, including the heart. It is clear that they are involved in synchronization of vascular function and cardiac metabolism however, the downstream effector genes have yet to be identified. To evaluate the function of mPer2 in post-infarct myocardial remodeling, we used an mPer2 mutant mouse which lacks functional mPer2 protein (mPer2-KO). In anesthetized, mechanically ventilated wild-type (WT) and mPer2-KO mice, Myocardial infarction was induced by permanent ligation of the left anterior descending coronary artery. Our data reveal that, although there is no difference in the initial area at risk between the WT and mPer2-KO mouse hearts, at 4 days post-MI there is a 50% reduction of infarct size in mPer2-KO mice compared to WT. This is coincident with a 40% increase in vascular density, 25% less macrophage infiltration, and 34% less apoptosis in the infarct zone. Cytokine array analysis showed 3-fold increase in IGFBP-3 and -5 and a 90% increase in SDF-1α, IL12p70, and lymphotactin in mPer2-KO relative to WT at 4 days post-MI. Conversely, in mPer2-KO the levels of L-selectin, sTNFRII, and IL-6 were approx. 70% less than the WT. These data suggest that mice lacking mPer2 protein have enhanced activation of anti-apoptotic and hypertrophic pathways, augmented chemotaxis for reparative cells, and blunted production of adverse inflammatory mediators post-MI. We conclude that deletion of the mPER2 gene is cardioprotective. Further mechanistic studies are being conducted to understand the signaling pathways that afford this protection. Long-term studies are also in progress to determine the duration of these protective effects and whether cardiac function is altered. Understanding the complex interactions between circadian rhythms and cardiovascular disease may provide insights into potential preventative and therapeutics for susceptible populations.