br Conclusion br Acknowledgements This work was

Conclusion
Acknowledgements This work was supported by R01 HL127386 (Niklason) and 1R01 HL128406-01A1 (Dardik), and by an unrestricted research gift from Humacyte Inc. KLL was supported by F30HL143880. KLL and EQ were supported by T32 GM007205. LEN is a founder and shareholder in Humacyte, Inc, which is a regenerative medicine company. Humacyte produces engineered blood vessels from allogeneic smooth muscle LY2606368 for vascular surgery. LEN's spouse has equity in Humacyte, and LEN serves on Humacyte's Board of Directors. LEN is an inventor on patents that are licensed to Humacyte and that produce royalties for LEN. LEN has received an unrestricted research gift to support research in her laboratory at Yale.
Introduction Chronic hyperglycemia during diabetes mellitus (DM) is associated with high levels of reactive oxygen species (ROS) and enhanced cardiomyocytes apoptosis [1]. Currently, it is well-accepted that cardiomyocytes-induced apoptosis is an indispensable factor for the development of diabetic cardiomyopathy and subsequent heart failure, in both type 1 and type 2 DM (T1DM and T2DM, respectively) in human and induced-animal models [1], [2], [3], [4]. Generally, a major hallmark of diabetic cardiomyopathy is the impeded systolic and diastolic function due to an early loss of contractile unit and late remodeling events including fibrosis and pathological hypertrophy [2], [5], [6], [7], [8]. Interestingly and during both phases of the diabetic cardiomyopathy observed in T1 and T2 DM, cardiomyocytes apoptosis involves both the intrinsic (mitochondria) and extrinsic ([fas/Fas ligand)-mediated cell death [9], [10], [11], [12], [13], [14], [15]. In the extrinsic cell death pathway, the binding of FasL (or the agonist) to Fas receptor initiates a cascade of events that eventually lead to activation of caspase-8, which in turn activate caspase-3, directly or indirectly, through the release of mitochondrial cytochrome c, in a step that is mediated by the cleavage of Bid [13]. However, although it was shown to up-regulate TLR4 [16], the precise mechanism by which diabetes or hyperglycemia induces Fas/FasL cell death is still under investigation and not clear yet. The nuclear factor of activated T cells (NFAT) is a family of four members transcriptional factors (NFAT1–4), which all are expressed in the mammalian's heart [17], has been recently viewed as activators of FasL promoter and potent inducer of pathological cardiac hypertrophy [18], [19]. All NFAT members are sequestered in the cytoplasm under the physiological condition as they are phosphorylated [19]. However, the nuclear translocation and transcriptional activity of NFAT members are induced by dephosphorylation due to activation of calcineurin in response to an increase in intracellular levels of ROS Ca+2 [19]. Hyperglycemia increases intracellular Ca+2 levels in the cardiomyocyte by several mechanisms [20], [21], [22]. Overexpression of sarcoplasmic reticulum Ca (2+)-ATPase (SERCA2a) improves myocardial contractility in T1DM cardiomyopathy by reducing intracellular Ca+2 levels [21]. Additionally and among all NFAT members, hyperglycemia or T1DM activate- NFAT4 transcriptional activity in the vascular smooth muscle, cerebral arteries, retina, and aorta of animals [21], [22], [23], [24], [25], [26]. Hence, these data strongly suggest that sustained hyperglycemia observed during DM may induce Fas/FasL cell death in the hearts by activation of Ca+2/calcineurin/NFAT4 axis, an effect that needs further investigation which may have therapeutic potential. On the other hand, the prevalence of chronic disorders including cardiovascular disorders of idiopathic origin has been suddenly increased our industrialized societies with a big shift in our diet toward food rich in omega-6 polyunsaturated fatty acids (n6-PUFAs) [27]. Major resources if n-6 PUFAs in our diet is linoleic acid (LA) (18∶2n-6) obtained from such sunflower, safflower, and corn oils (CO) (Beam et al., 2012). Indeed, the pathological role of n-6 PUFAs in the induction and progression of cardiovascular disorders has been extensively viewed and confirmed during the last decades [27], [28], [29], [30], [31].