Mutations in one of the genes encoding the components of. A and D: The hearts were fixed, embedded, and sectioned. Two months after STZ injection, the mRNA levels of CHOP (A), GRP78 (B), and XBP1 (C) were quantified in heart tissues by real-time RT-PCR. Another protein, p40phox, has been implicated in the regulation of the NADPH oxidase, but no individual with a … Epub 2018 Nov 15. Cardiomyocyte cross-sectional area was measured with an image quantitative digital analysis system. Deficiency of Rac1 Blocks NADPH Oxidase Activation, Inhibits Endoplasmic Reticulum Stress, and Reduces Myocardial Remodeling in a Mouse Model of Type 1 Diabetes, Diabetic cardiomyopathy: the search for a unifying hypothesis, Hypoxia activates NADPH oxidase to increase [ROS]i and [Ca2+]i through the mitochondrial ROS-PKCepsilon signaling axis in pulmonary artery smooth muscle cells, Molecular mechanisms of angiotensin II-mediated mitochondrial dysfunction: linking mitochondrial oxidative damage and vascular endothelial dysfunction, Link between mitochondria and NADPH oxidase 1 isozyme for the sustained production of reactive oxygen species and cell death, Rac1 is required for cardiomyocyte apoptosis during hyperglycemia, Cross talk between mitochondria and superoxide generating NADPH oxidase in breast and ovarian tumors, Protection of cardiac mitochondria by overexpression of MnSOD reduces diabetic cardiomyopathy, IGF-1 overexpression inhibits the development of diabetic cardiomyopathy 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diabetes-induced vascular injury, NADPH oxidase-dependent redox signalling in cardiac hypertrophy, remodelling and failure, Contrasting roles of NADPH oxidase isoforms in pressure-overload versus angiotensin II-induced cardiac hypertrophy, Critical role of the NAD(P)H oxidase subunit p47phox for left ventricular remodeling/dysfunction and survival after myocardial infarction, Regulation of NADPH oxidases: the role of Rac proteins, Pressure overload-induced myocardial hypertrophy in mice does not require gp91phox, Glycated proteins stimulate reactive oxygen species production in cardiac myocytes: involvement of Nox2 (gp91phox)-containing NADPH oxidase, Downregulation of NADPH oxidase, antioxidant enzymes, and inflammatory markers in the heart of streptozotocin-induced diabetic rats by N-acetyl-L-cysteine, Apocynin, NADPH oxidase, and vascular cells: a complex matter, The pathogenesis of myocardial fibrosis in the setting of diabetic cardiomyopathy, Increased myocardial NAD(P)H oxidase-derived superoxide causes the exacerbation of postinfarct heart failure in type 2 diabetes, Osteopontin: role in extracellular matrix deposition and myocardial remodeling post-MI, Transgenic activation of the kallikrein-kinin system inhibits intramyocardial inflammation, endothelial dysfunction and oxidative stress in experimental diabetic cardiomyopathy, Adiponectin improves cardiomyocyte contractile function in db/db diabetic obese mice, Endoplasmic reticulum stress in diabetic hearts abolishes erythropoietin-induced myocardial protection by impairment of phospho-glycogen synthase kinase-3beta-mediated suppression of mitochondrial permeability transition, Inhibition of cardiac remodeling by pravastatin is associated with amelioration of endoplasmic reticulum stress, Metallothionein alleviates cardiac dysfunction in streptozotocin-induced diabetes: role of Ca2+ cycling proteins, NADPH oxidase, poly(ADP-Ribose) polymerase and myosin heavy chain isozyme, Connectivity Mapping Identifies BI-2536 as a Potential Drug to Treat Diabetic Kidney Disease, circRNA_010383 Acts as a Sponge for miR-135a, and Its Downregulated Expression Contributes to Renal Fibrosis in Diabetic Nephropathy, CaM Kinase II-δ Is Required for Diabetic Hyperglycemia and Retinopathy but Not Nephropathy, ADA Standards of Medical Care in Diabetes, Institutional Subscriptions and Site Licenses, Special Podcast Series: Therapeutic Inertia, Special Podcast Series: Influenza Podcasts, http://diabetes.diabetesjournals.org/cgi/content/full/db09-1800/DC1, http://creativecommons.org/licenses/by-nc-nd/3.0/. Activation of fibroblasts with limited proliferative capacity undergoes a conversion to myofibroblasts, leading to the formation of fibrosis (43). Violi F, Carnevale R, Loffredo L, Pignatelli P, Gallin JI. ROS is mainly produced by mitochondria and NADPH oxidase in cardiomyocytes. The NADPH oxidase complex catalyzes electron transfer from NADPH to molecular oxygen and thus generates superoxide, the precursor of H 2 O 2 and other ROS (29, 46). Consistently, STZ-induced diabetic animals showed a significant reduction of +dF/dtmax and −dF/dtmin compared with nondiabetic ones. The present study used mice with cardiomyocyte-specific Rac1 knockout to investigate the role of Rac1 signaling in myocardial remodeling in chronic diabetes. These effects were associated with a normalization of ER stress markers' expression and inflammatory response in diabetic hearts. Cell Rep. 2019 Apr 2;27(1):238-254.e6. Front Cell Infect Microbiol. contributed equally to the work. We recently showed that deficiency of Rac1 attenuates myocardial dysfunction in diabetic hearts (8). As pa- deficiency of NADPH oxidase subunits may be associated tients with p47phox deficiency disclosed higher generation of with a different rate of ROS formation. Nicotinamide adenine dinucleotide phosphate oxidase 2 (Nox2) deficiency converts M1 macrophages to an overactive state. Genetic disorders coupled to ROS deficiency. 2A and B). Thus, deficiency of Rac1 not only blocks the translocation of p67pho to the membrane, NADPH oxidase activation, and ROS production, but also inhibits its expression in diabetic hearts. Blood. The mice were considered diabetic and used for the study only if they had hyperglycemia (≥15 mmol/l) at 72 h after STZ injection, whereas citrate buffer–treated mice were used as a nondiabetic control (blood glucose <12 mmol/l). This makes red blood cells more susceptible to reactive oxygen species, ultimately causing anemia, spontaneous abortions, and problems with fetuses [ 9 ]. If ER stress is prolonged or overwhelming, however, it can induce cell death through CHOP and/or other pathways. 2018 Feb;180(3):454-456. doi: 10.1111/bjh.14347. Adult male rats (Sprague-Dawley, 200 g body weight) were purchased from Charles River Labs. (e) Spinal cord invasion (arrow) in a patient with pulmonary aspergillosis. macrophage colony-stimulating factor (50 ng/mL)–differentiated bone marrow–derived macrophages (BMMs) were stimulated with interferon (IFN)-γ (10 ng/mL) and interleukin (IL)-4 (10 ng/mL) for 16 hours, to skew them toward M1 and M2 subsets, respectively. Consistent with a previous report (30), diabetes increased CHOP, XBP1, and GRP78 mRNA and/or protein expression in the heart, confirming the presence of ER stress. L.W. F: Mitochondrial superoxide production was increased in WT diabetic hearts, which was significantly decreased in Rac1 KO hearts. In the present study, we extended our experiments to examine the therapeutic potential of NADPH oxidase inhibition with apocynin for myocardial dysfunction in diabetic mice. The NADPH oxidase complex catalyzes electron transfer from NADPH to molecular oxygen and thus generates superoxide, the precursor of H 2 O 2 and other ROS (29, 46). NADPH oxidase is important in respiratory or oxidative burst results in rapid release of reactive oxygen species such as superoxide CGD patients lack the oxidative burst can only use peroxide from microorganisms to make reactive oxygen species NADPH oxidase deficiency in X-linked chronic granulomatous disease. Breeding pairs of C57BL/6 mice and mice bearing the modified Rac1 gene containing loxP sites (floxed Rac1) were purchased from The Jackson Laboratory. J.L., H.Z., and E.S. After induction of diabetes, apocynin, an inhibitor of NADPH oxidase, was administered to the control-treated and diabetes-treated groups in the drinking water (30 mg/kg/day) for 2 months. An ITAM-signaling pathway controls cross-presentation of particulate but not soluble antigens in dendritic cells. (A high-quality digital representation of this figure is available in the online issue. To test this hypothesis, we determined ER stress by analyzing ER stress markers' expression (CHOP, XBP1, and GRP78) (31). © 2010 by the American Diabetes Association. Selective inhibition of mitochondrial ROS has been shown to prevent diabetic cardiac changes in type 1 diabetic mice, confirming an important role of mitochondrial ROS (10). The mRNA levels of Col I (A), Col III (B), osteopontin (C), α-SMA (D), TGF-β1 (E), and TNF-α (F) were quantified in heart tissues by real-time RT-PCR. Glucose -6-phosphate dehydrogenase (G6PD) is needed to convert NADP+ into NADPH. -, Graham D. B., Stephenson L. M., Lam S. K., et al. Deficiency of Rac1 or apocynin administration reduced myocardial fibrosis and hypertrophy, resulting in improved myocardial function. ER stress was also observed in type 2 diabetic rats and compromised myocardial response to cytoprotective signaling (47). O.D., optical density. To investigate the role of Rac1 signaling in myocardial fibrosis, we first analyzed total collagen contents in diabetic hearts. Thank you for your interest in spreading the word about Diabetes. In a separate experiment, WT animals were divided into four groups (n = 8–12 in each group) that included control, control-treated, diabetes, and diabetes-treated groups. Deficiency of Rac1 also abrogated the increase of superoxide production in freshly isolated mitochondria from diabetic hearts on addition of pyruvate/malate (Fig. researched data. In response to STZ, the mRNA levels of TGF-β1, α-SMA, and osteopontin were significantly upregulated in WT or vehicle-treated hearts. T.P. deficiency of myeloperoxidase, and 7 patients with X-linked chronic granulomatous disease (CGD). Consistently, cardiomyocyte cross-sectional areas were significantly increased in diabetic compared with nondiabetic hearts, indicative of hypertrophy (Fig. 2017 Aug 25;7:373. doi: 10.3389/fcimb.2017.00373. A: Representative staining for collagen deposition is presented for intra-myocardium (IM), small vessel (SV), and big vessel (BV) from each group. All data were given as mean ± SD. The mechanism involves improved neovascularization through a reduction of ROS formation, preserved activation of the VEGF/NO angiogenic pathway, and improved functional activities of endothelial progenitor cells. In diabetes, more recent studies have shown that cardiac ER stress was induced and linked to cell death in STZ-induced type 1 diabetes, which may play a part in diabetic cardiomyopathy (30). Chronic granulomatous disease = NADPH oxidase deficiency This disease is characterized by increased susceptibility to catalase-positive organisms. Heropolitanska-Pliszka E, Berk K, Maciejczyk M, Sawicka-Powierza J, Bernatowska E, Wolska-Kusnierz B, Pac M, Dabrowska-Leonik N, Piatosa B, Lewandowicz-Uszynska A, Karpinska J, Zalewska A, Mikoluc B. J Clin Med. (An expanded research design and methods section is available in the online appendix at http://diabetes.diabetesjournals.org/cgi/content/full/db09-1800/DC1.). Diabetic cardiomyopathy has been defined as ventricular dysfunction that occurs in the absence of changes in blood pressure and coronary artery disease (1). Similarly, incubation of apocynin inhibited ER stress in high glucose–stimulated ARVCs (Fig. Vascular Biology of Superoxide-Generating NADPH Oxidase 5-Implications in Hypertension and Cardiovascular Disease. One common mutation is an autosomal recessive mutation, which is where both copies of a chromosome need to possess the same mutation for the disease to occur. The collagen deposition was present in both intra-myocardial and peri-vascular areas (Fig. 1C and D), which were dramatically reduced in Rac1-ko mice. Kim HJ, Kim D, Yoon H, Choi CS, Oh YS, Jun HS. Reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is an enzyme that catalyzes the production of superoxide (O 2−) from oxygen and NADPH, according to the following reaction : NADPH +2 O 2 → NADP + + H + +2 O 2 −. Rac1 has previously been suggested to be mediators of inflammation (27). A progressive improvement of the areas of consolidation in the left and right lungs, especially for the right lobes, is observed. 2B and C). Get the latest public health information from CDC: https://www.coronavirus.gov, Get the latest research information from NIH: https://www.nih.gov/coronavirus, Find NCBI SARS-CoV-2 literature, sequence, and clinical content: https://www.ncbi.nlm.nih.gov/sars-cov-2/. It is important to mention that the present study demonstrated that Rac1 in cardiomyocytes contributes to fibrosis, since the levels of Rac1 protein are not altered in cardiac fibroblasts from cardiomyocyte-specific Rac1 knockout mice compared with their WT littermates. Furthermore, Rac1/NADPH oxidase signaling has also been demonstrated to directly induce cardiac hypertrophy (12,13) and skin fibrosis (14,15). Thus, the present study extends the role of Rac1 via NADPH oxidase to the development of diabetic cardiac hypertrophy. Deficiency of NADPH oxidase activity in chronic granulomatous disease. Several sections of heart (5 μm thick) were prepared and stained with hematoxylin and eosin and a saturated solution of picric acid containing 1% Sirius red for collagen deposition (18). All animals responded to STZ treatment, and no animal died or was excluded from the study. 1997 Mar;34(2):147-50. doi: 10.1016/s0163-4453(97)92509-3. Consistently, the mRNA levels of Col I and III in hearts from diabetic Rac1-ko and apocynin-treated mice were much lower than those in diabetic WT and vehicle-treated mice, respectively (Figs. (a, b) Cerebral invasion (arrows) in a patient with invasive pulmonary aspergillosis. Importantly, myocardial function was significantly improved in apocynin-treated STZ mice compared with STZ controls (Fig. indicate that NADPH oxidase contributes to DM-induced ROS increase. In a separate experiment, wild-type diabetic mice were treated with vehicle or apocynin in drinking water. G and H: Representative immunohistological stainings for TGF-β1 (G) and TNF-α (H) from four to six different hearts in each group (yellow-brown signal). NADPH oxidase deficiency underlies dysfunction of aged CD8+ Tregs Immune aging results in progressive loss of both protective immunity and T cell-mediated suppression, thereby conferring susceptibility to a combination of immunodeficiency and chronic inflammatory disease. A value of P < 0.05 was considered statistically significant. The change in fibroblast properties is initiated by TGF-β1, which stimulates the expression of genes that are characteristic of myofibroblasts, including α-SMA and osteopontin. Enter multiple addresses on separate lines or separate them with commas. 7E), indicative of induction of ER stress and activation of PERK and ATF-6 pathways (31). macrophage colony-stimulating factor (50 ng/mL)–differentiated bone marrow–derived macrophages (BMMs) were stimulated with interferon (IFN)-γ (10 ng/mL) and interleukin (IL)-4 (10 ng/mL) for 16 hours, to skew them toward M1 and M2 subsets, respectively. Sections of heart were stained with hematoxylin and eosin and a saturated solution of picric acid containing 1% Sirius red for collagen deposition (see research design and methods). Diabetic mice had higher plasma glucose levels (20 – 30 mmol/l) than nondiabetic control mice (<12 mmol/l) 72 h after STZ injection. (c) Cerebellar aspergillosis (arrow). In this regard, overexpression of active Rac1 induces cardiomyocyte hypertrophy (13), and cardiomyocyte specific Rac1 knockout prevents angiotensin-induced hypertrophy in mice (12). The outline of 200 cardiomyocytes was traced in each section. These studies suggest that ER stress may play a part in diabetic heart diseases. Wild-type mice were rendered diabetic by STZ injection, and apocynin was administrated in the drinking water for 2 months. CONCLUSIONS Rac1 via NADPH oxidase activation induces myocardial remodeling and dysfunction in diabetic mice. E.S. ... (at pH 5.5 and in the presence of 0.5 mM Mn++), NADPH oxidase activity increased fourfold with phagocytosis and was six-fold higher than with NADH. Cultured ARVCs were transfected with siRNA specific for Nox2 and Nox4, respectively, and then incubated with normal (5.5 mmol/l) or high glucose (33 mmol/l) for 24 h. A scrambled siRNA was used as a control. © 2021 by the American Diabetes Association. Reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is an enzyme that catalyzes the production of superoxide (O 2−) from oxygen and NADPH, according to the following reaction : NADPH +2 O 2 → NADP + + H + +2 O 2 −. 1B), and ROS production (Fig. ANOVA followed by Newman-Keuls test was performed for multigroup comparisons. M.A. Role of Rac1/NADPH oxidase in myocardial fibrosis. In people with genetic G6PD deficiency, NADPH production is insufficient. Humans without CGD: Production of H2O2 via respiratory burst is >>> catalase produced by organisms → organisms are overwhelmed + die However, this effect of apocynin was not observed in nondiabetic hearts. It is likely that Rac1 in fibroblasts, albeit speculation, also plays a role in myocardial fibrosis in diabetes, since mice containing a fibroblast-specific deletion of Rac1 showed resistance to the bleomycin-induced model of skin fibrosis (15) and impaired myofibroblast formation in the dermal punch model of cutaneous wound healing (14). Arterioscler Thromb Vasc Biol. NADPH oxidase is important in respiratory or oxidative burst results in rapid release of reactive oxygen species such as superoxide CGD patients lack the oxidative burst can only use peroxide from microorganisms to make reactive oxygen species A cross-talk between mitochondria and NADPH oxidase has been suggested to sustain cellular ROS production under stresses (5–9). Similar to the finding of cardiomyocyte cross-sectional areas, induction of cardiac fetal gene expression (atrial natriuretic peptide [ANP] and β-MHC, markers of cardiac hypertrophy) was significantly reduced in Rac1-ko mice compared with their WT hearts in response to diabetes (Fig. Two months later, NADPH oxidase activation and expression and ROS production in heart tissues were measured. We therefore hypothesized that blocking Rac1 signaling could prevent ER stress in diabetic hearts. *P < 0.05 vs. nondiabetes (ND) in WT; #P < 0.05 vs. diabetes (DM) in WT. The mechanism involves improved neovascularization through a reduction of ROS formation, preserved activation of the VEGF/NO angiogenic pathway, and improved functional activities of endothelial progenitor cells. NADPH oxidase (NOX) plays a pivotal role in the production of ROS, and the defect of its different subunits leads to the development of chronic granulomatous disease (CGD). Similarly, deficiency of Rac1 also inhibited diabetes-induced TGF-β1 protein in the myocardium (Fig. RESULTS In diabetic hearts, NADPH oxidase activation, its subunits' expression, and reactive oxygen species production were inhibited by Rac1 knockout or apocynin treatment. Levels of ER stress makers (phosphorylated PERK, IRE-1, and eIF2α) were significantly elevated in cardiomyocyte from type 2 diabetic db/db mice, presumably contributing to cardiomyocyte dysfunction (46). (d) Invasive pulmonary aspergillosis.  |  Diabetes was induced by injection of STZ in Rac1-ko (KO) and their WT littermates. In people with genetic G6PD deficiency, NADPH production is insufficient. 8). 2015 Dec;6:135-156. doi: 10.1016/j.redox.2015.07.009. ROS are small oxygen-derived molecules with an important role in various biological processes (physiological or pathological). Collagen deposition is stained as red color. In nondiabetic mice, there were no changes in mRNA levels of TGF-β1, α-SMA, and osteopontin between Rac1-ko and WT hearts and between vehicle and apocynin-treated hearts. (A high-quality digital representation of this figure is available in the online issue.). 2007;204(12):2889–2897. researched data. Thus, Rac1 and NADPH oxidase activation play a critical role in myocardial remodeling during the development of diabetic cardiomyopathy, and this action of Rac1/NADPH oxidase may be associated with ER stress and inflammatory response in diabetic hearts. The top panel is the representative Western blot for Rac1, p67phox, and gp91phox from three out of five to six different hearts in each group and the lower panel is the quantification of Rac1, p67phox, and gp91phox. Oxidative stress is involved in ER stress induction, which contributes to myocardial dysfunction (29). Mice with cardiomyocyte-specific Rac1 knockout (Rac1-ko) were generated by crossing the floxed Rac1 mice with mice overexpressing Cre under the control of α-MHC, as we recently described (8). To characterize whether the role of Rac1 signaling in ER stress could be reproduced by high glucose levels, we extended our analyses to cardiomyocytes. The top panel is the representative blot from at least three different cell cultures and the lower panel is the quantification of phosphorylated PERK, cleaved ATF-6, and GRP78 protein. In chronic granulomatous disease, there’s a mutation in the genes that code for NADPH oxidase, so the enzyme is less functional. Chronic granulomatous disease (CGD), also known as Bridges–Good syndrome, chronic granulomatous disorder, and Quie syndrome, is a diverse group of hereditary diseases in which certain cells of the immune system have difficulty forming the reactive oxygen compounds (most importantly the superoxide radical due to defective phagocyte NADPH oxidase) used to kill certain ingested pathogens. G: Thioredoxin reductase activity was preserved in Rac1 knockout diabetic hearts. Intrapulmonary Mycobacterium avium infection as the first manifestation of chronic granulomatous disease. Generation of the superoxide in vascular NADPH occurs by a one-electron reduction of oxygen via the gp91phox subunit, using reduced NADPH as the electron donor. We further demonstrated that high glucose–induced ER stress was associated with activation of PERK- and ATF-6–dependent pathways. Hearts were excised, washed with saline solution, and placed in 10% formalin. In addition to a direct pro-hypertrophic role of Rac1 in cardiomyocyte, the anti-hypertrophic effects of Rac1 knockout and NADPH oxidase inhibition may also partly result from the prevention of cardiomyocyte apoptosis, which otherwise will lead to compensative hypertrophy, since deficiency of Rac1 or inhibition of NADPH oxidase reduces cardiomyocyte apoptosis in diabetic hearts . Glucose -6-phosphate dehydrogenase (G6PD) is needed to convert NADP+ into NADPH. Cultured adult rat cardiomyocytes were transfected with gp91phox siRNA, Nox4 siRNA, or a scrambled siRNA as a control and then incubated with normal glucose (NG, 5.5 mmol/l) or high glucose (HG, 33 mmol/l) for 24 h. NADPH oxidase activity (C and E) and superoxide production (D and F) were measured in cardiomyocytes. Adane B, Ye H, Khan N, Pei S, Minhajuddin M, Stevens BM, Jones CL, D'Alessandro A, Reisz JA, Zaberezhnyy V, Gasparetto M, Ho TC, Kelly KK, Myers JR, Ashton JM, Siegenthaler J, Kume T, Campbell EL, Pollyea DA, Becker MW, Jordan CT. ARVCs were infected with Ad-RacN17, an adenoviral vector expressing a dominant-negative mutant of Rac1, which specifically blocks Rac1 activation (32), or Ad-gal as an adenoviral control and were then incubated with normal (5.5 mmol/l) or high glucose (33 mmol/l) for 24 h. High glucose significantly increased GRP78 protein, phosphorylated PERK, and cleaved ATF-6 (50 kDa) in ARVCs (Fig. In diabetes, it remains unclear whether Rac1 and NADPH oxidase are involved in diabetic cardiac hypertrophy. Phagocytic neutrophils from patients with CGD were markedly The costs of publication of this article were defrayed in part by the payment of page charges. contributed to discussion, reviewed/edited manuscript. 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