Empagliflozin groups showed smaller atherosclerotic plaque areas in the aortic arch/valve, and lower insulin resistance and inflammation markers (TNF-, interleukin [IL]-6, monocyte chemoattractant protein-1, etc

Empagliflozin groups showed smaller atherosclerotic plaque areas in the aortic arch/valve, and lower insulin resistance and inflammation markers (TNF-, interleukin [IL]-6, monocyte chemoattractant protein-1, etc.) compared with glimepiride group. or due to direct cardiovascular e?ects, or both. To examine whether SGLT-2 inhibitors operate directly on cardiac speci?c pathophysiological mechanisms without interference of other mediating factors, including plasma circulating glucose and insulin, isolated cardiac cell and organ studies are required.3) Recently, Desoxyrhaponticin Lim et al.4) reported that long-term diet for 4 weeks with canagliflozin had smaller infarct sizes in isolated Langendorff-perfused hearts from diabetic and nondiabetic rats. However, interestingly, direct treatment of isolated nondiabetic rat hearts with canagliflozin had no impact on infarct size. They proposed that this infarct-sparing effect of long-term treatment with canagliflozin results from either a glucose-independent effect or up-regulation Rabbit polyclonal to Caspase 3.This gene encodes a protein which is a member of the cysteine-aspartic acid protease (caspase) family.Sequential activation of caspases plays a central role in the execution-phase of cell apoptosis.Caspases exist as inactive proenzymes which undergo pro of cardiac prosurvival pathways. While SGLT-2 has not been detected at all in the heart, increasing evidence demonstrate the presence of SGLT-2 in non-cardiac endothelial cells. Several studies have reported that SGLT-2 inhibitors directly alter endothelial cells and easy muscle cells by reducing SGLT-2-mediated glucose uptake, ameliorating vasorelaxation, increasing adenosine monophosphate-activated protein kinase (AMPK) activity and preventing mitochondrial dysfunction in hyperglycemic and in?amed vascular cells.3) In this issue of em Korean Circulation Journal /em , Lee et al.5) elaborately demonstrated that dapagliflozin (1 mg/kg/day) had an anti-atherosclerotic effect by reducing percent area stenosis by optical coherence tomography imaging and atheroma burden by immunohistochemistry staining in non-diabetic rabbit abdominal aorta injury model. They focused on the anti-inflammatory response of dapagliflozin, assessed by macrophage infiltration and polarization (i.e., inducible nitric oxide synthase/arginase-1 ratio) and tumor necrosis factor (TNF)- expression in the injured aorta tissue, which was associated with the attenuated expression of Toll-like receptor 4/nuclear factor-kappa B signaling pathway. In fact, recent reports have shown the suppression of atherosclerosis or endothelial dysfunction in response to SGLT-2 inhibitor administration. Han et al.6) investigated the effect of empagliflozin around the progression of atherosclerosis in ApoE?/? mice fed a western diet. Empagliflozin groups showed smaller atherosclerotic plaque areas in the aortic arch/valve, and lower insulin resistance and inflammation markers (TNF-, interleukin [IL]-6, monocyte chemoattractant protein-1, etc.) compared with glimepiride group. Other researcher also reported that SGLT-2 inhibitor administration reduced reactive oxygen species generation, which might decrease the expression of inflammatory molecules (IL-1, IL-18, NLRP3 inflammasome) in the abdominal aorta of streptozotocin-induced diabetic mice.7) Although the anti-atherosclerotic effect of SGLT-2 inhibitors can play a role to prevent CVD events in T2DM patients, the observed reductions of cardiovascular outcomes in CVOTs were much earlier and powerful than would be expected by Desoxyrhaponticin an anti-atherosclerotic effect. These findings have led to speculation about the potential underlying mechanisms involved in direct cardiac protection, even though SGLT-2 does not express in cardiomyocytes (CMs). Suggested mechanisms include the inhibition of L-type Ca2+ channel and/or Na+/H+ exchanger 1 (NHE-1), which can reduce cytosolic (Ca2+) and (Na+) and increased mitochondrial (Ca2+) in CMs.8) These ?ndings may re? ect improved mitochondrial capacity to synthesize ATP and target oxidants, which would be Desoxyrhaponticin bene?cial to restore the energetic state of CMs that is known to be decreased in heart failure. In molecular binding studies, SGLT-2 inhibitors exhibit high binding affinities with the extracellular Na+-binding site of the NHE-1, which indicate that this SGLT-2 inhibitors exert an off-target effect on the NHE-1.3) Recently, Juni et al.9) reported that cardiac microvascular endothelial cells (CMECs) confer a direct positive effect on contraction and relaxation of CMs, an effect that requires nitric oxide, is diminished after CMEC stimulation with TNF-, and Desoxyrhaponticin is restored by empagliflozin. In addition, cardiac ?broblasts are valuable targets for therapeutic applications due to their role in cardiac remodeling after MI. Pre-incubation with dapagliflozin (0.3C0.5 M) showed attenuation of lipopolysaccharide-induced upregulation of inflammasome complex such as NLRP3, ASC, and Desoxyrhaponticin caspase-1 mRNA levels in cardiac fibroblasts, which was mediated through increased AMPK activation without the involvement of SGLT.10) These mechanisms are not separate entities but are all intrinsically interrelated, and together may induce contractile, vascular and mitochondrial dysfunction, and cell death in the heart, which may evolve into left ventricular concentric or eccentric hypertrophy and heart failure. Bridging the gap from treating diabetes by lowering blood sugar to simultaneously reducing the risk of CVDs with a single medicine is a great leap forward for diabetes treatment with significant implications for endocrinologists and cardiologists. In this respect, SGLT-2 inhibitors are regarded as a promising option, when we are faced with the challenge.