scholarly journals Substance P Antagonism Prevents Chemotherapy-Induced Cardiotoxicity

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1732
Author(s):  
Ashiq Legi ◽  
Emma Rodriguez ◽  
Thomas K. Eckols ◽  
Cyrus Mistry ◽  
Prema Robinson
Keyword(s):  
Oxidative Stress ◽  
Body Weight ◽  
Substance P ◽  
Group Treatment ◽  
Cardiac Dysfunction ◽  
Annexin V ◽  
Heart Weight ◽  
Cardiomyocyte Hypertrophy ◽  
Functional Parameters ◽  
Cardiac Apoptosis

Background: Doxorubicin (DOX), used in chemotherapeutic regimens in many cancers, has been known to induce, cardiotoxicity and life-threatening heart failure or acute coronary syndromes in some patients. We determined the role of Substance P (SP), a neuropeptide and its high affinity receptor, NK-1R in chemotherapy associated cardiotoxicity in mice. We determined if NK-1R antagonism will prevent DOX-induced cardiotoxicity in vivo. Methods: C57BL/6 mice (6- week old male) were injected intraperitoneally with DOX (5 mg per kilogram of body weight once a week for 5 weeks) with or without treatment with aprepitant (a NK-1R antagonist, Emend, Merck & Co., Kenilworth, NJ, USA). Five different dosages of aprepitant were administered in the drinking water five days before the first injection of DOX and then continued until the end of the experiment. Each of these 5 doses are as follows; Dose 1 = 0.9 µg/mL, Dose 2 = 1.8 µg/mL, Dose 3 = 3.6 µg/mL, Dose 4 = 7.2 µg/mL, Dose 5 = 14.4 µg/mL. Controls consisted of mice injected with PBS (instead of DOX) with or without aprepitant treatment. The experiment was terminated 5 weeks post-DOX administration and various cardiac functional parameters were determined. Following euthanization, we measured heart weight to body weight ratios and the following in the hearts, of mice treated with and without DOX and aprepitant; (a) levels of SP and NK1R, (b) cardiomyocyte diameter (to determine evidence of cardiomyocyte hypertrophy), (c) Annexin V levels (to determine evidence of cardiac apoptosis), and (d) ratios of reduced glutathione (GSH) to oxidized glutathione (GSSG) (to determine evidence of oxidative stress). Results: We demonstrated that the levels of SP and NK1R were significantly increased respectively by 2.07 fold and 1.86 fold in the hearts of mice treated with versus without DOX. We determined that DOX-induced cardiac dysfunction was significantly attenuated by treatment with aprepitant. Cardiac functional parameters such as fractional shortening (FS), ejection fraction (EF) and stroke volume (SV) were respectively decreased by 27.6%, 21.02% and 21.20% compared to the vehicle treated group (All, p < 0.05, ANOVA). Importantly, compared to treatment with DOX alone, treatment with lower doses of aprepitant in DOX treated mice significantly reduced the effects of DOX on FS, EF and SV to values not significantly different from sham (vehicle treated) mice (All, p < 0.05, ANOVA). The levels of, apoptosis marker (Annexin V), oxidative stress (ratio of GSH with GSSG) and cardiomyocyte hypertrophy were respectively increased by 47.61%, 91.43% and 47.54% in the hearts of mice treated with versus without DOX. Compared to the DOX alone group, treatment with DOX and Dose 1, 2 and 3 of aprepitant significantly decreased the levels of each of these parameters (All p < 0.05, ANOVA). Conclusions: Our studies indicate that the SP/NK1-R system is a key mediator that induces, DOX-induced, cardiac dysfunction, cardiac apoptosis, cardiac oxidative stress and cardiomyocyte hypertrophy. These studies implicate that NK-1R antagonists may serve as a novel therapeutic tool for prevention of chemotherapy induced cardiotoxicity in cancer.

Genistein prevents isoproterenol-induced cardiac hypertrophy in rats

2012 ◽  
Vol 90 (8) ◽  
pp. 1117-1125 ◽  
Author(s):  
Subir Kumar Maulik ◽  
Pankaj Prabhakar ◽  
Amit Kumar Dinda ◽  
Sandeep Seth
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Body Weight ◽  
Nitric Oxide Synthase ◽  
Cardiac Hypertrophy ◽  
Weight Ratio ◽  
Left Ventricular ◽  
Heart Weight ◽  
Once Daily ◽  
Oxide Synthase

Genistein, an isoflavone and a rich constituent of soy, possesses important regulatory effects on nitric oxide (NO) synthesis and oxidative stress. Transient and low release of NO by endothelial nitric oxide synthase (eNOS) has been shown to be beneficial, while high and sustained release by inducible nitric oxide synthase (iNOS) may be detrimental in pathological cardiac hypertrophy. The present study was designed to evaluate whether genistein could prevent isoproterenol-induced cardiac hypertrophy in male Wistar rats (150–200 g, 10–12 weeks old) rats. Isoproterenol (5 mg·(kg body weight)–1) was injected subcutaneously once daily for 14 days to induced cardiac hypertrophy. Genistein (0.1 and 0.2 mg·kg–1, subcutaneous injection once daily) was administered along with isoproterenol. Heart tissue was studied for myocyte size and fibrosis. Myocardial thiobarbituric acid reactive substances (TBARS), glutathione (GSH), superoxide dismutase (SOD), catalase levels, and 1-OH proline (collagen content) were also estimated. Genistein significantly prevented any isoproterenol-induced increase in heart weight to body weight ratio, left ventricular mass (echocardiographic), myocardial 1-OH proline, fibrosis, myocyte size and myocardial oxidative stress. These beneficial effects of genistein were blocked by a nonselective NOS inhibitor (L-NAME), but not by a selective iNOS inhibitor (aminoguanidine). Thus, the present study suggests that the salutary effects of genistein on isoproterenol-induced cardiac hypertrophy may be mediated through inhibition of iNOS and potentiation of eNOS activities.

scholarly journals Bawei Chenxiang Wan Ameliorates Cardiac Hypertrophy by Activating AMPK/PPAR-α Signaling Pathway Improving Energy Metabolism

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiaoying Zhang ◽  
Zhiying Zhang ◽  
Pengxiang Wang ◽  
Yiwei Han ◽  
Lijun Liu ◽  
...  
Keyword(s):  
Body Weight ◽  
Energy Metabolism ◽  
Cardiac Hypertrophy ◽  
Heart Function ◽  
Weight Ratio ◽  
Tibetan Medicine ◽  
Heart Weight ◽  
Cardiomyocyte Hypertrophy ◽  
Body Weight Ratio ◽  
Cross Sectional

Bawei Chenxiang Wan (BCW), a well-known traditional Chinese Tibetan medicine formula, is effective for the treatment of acute and chronic cardiovascular diseases. In the present study, we investigated the effect of BCW in cardiac hypertrophy and underlying mechanisms. The dose of 0.2, 0.4, and 0.8 g/kg BCW treated cardiac hypertrophy in SD rat model induced by isoprenaline (ISO). Our results showed that BCW (0.4 g/kg) could repress cardiac hypertrophy, indicated by macro morphology, heart weight to body weight ratio (HW/BW), left ventricle heart weight to body weight ratio (LVW/BW), hypertrophy markers, heart function, pathological structure, cross-sectional area (CSA) of myocardial cells, and the myocardial enzymes. Furthermore, we declared the mechanism of BCW anti-hypertrophy effect was associated with activating adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK)/peroxisome proliferator–activated receptor-α (PPAR-α) signals, which regulate carnitine palmitoyltransferase1β (CPT-1β) and glucose transport-4 (GLUT-4) to ameliorate glycolipid metabolism. Moreover, BCW also elevated mitochondrial DNA-encoded genes of NADH dehydrogenase subunit 1(ND1), cytochrome b (Cytb), and mitochondrially encoded cytochrome coxidase I (mt-co1) expression, which was associated with mitochondria function and oxidative phosphorylation. Subsequently, knocking down AMPK by siRNA significantly can reverse the anti-hypertrophy effect of BCW indicated by hypertrophy markers and cell surface of cardiomyocytes. In conclusion, BCW prevents ISO-induced cardiomyocyte hypertrophy by activating AMPK/PPAR-α to alleviate the disturbance in energy metabolism. Therefore, BCW can be used as an alternative drug for the treatment of cardiac hypertrophy.

Abstract P109: Angiotensin-(1-9) Reverses Cardiac Dysfunction in a Model of Angiotensin II-Induced Hypertensive Heart Disease by Acting as a Positive Inotrope

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Katrin Nather ◽  
Mónica Flores-Muñoz ◽  
Lauren Wills ◽  
Rhian M Touyz ◽  
Christopher M Loughrey ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Cardiac Dysfunction ◽  
Therapeutic Potential ◽  
Hypertensive Heart Disease ◽  
Heart Weight ◽  
Cardiomyocyte Hypertrophy ◽  
Collagen Iii ◽  
Angiotensin Type 2 Receptor ◽  
Developed Pressure

Angiotensin II (AngII) is involved in the pathophysiology of cardiovascular diseases (CVD) such as hypertension and heart failure. The counter-regulatory axis of the renin angiotensin system is centred on ACE 2 generating angiotensin-(1-7) [Ang-(1-7)] opposing the pathological actions of AngII in the heart. We recently showed that angiotensin-(1-9) [Ang-(1-9)] is part of this axis potentially acting via the angiotensin type 2 receptor to inhibit AngII-induced cardiomyocyte hypertrophy in vitro and cardiac remodelling in the SHRSP rat. Here, we assessed whether Ang-(1-9) can reverse chronic AngII-induced cardiac pathology. C57BL/6J mice were infused with H 2 O (control) or 48μg/kg/hr AngII for 2 weeks to induce cardiac contractile dysfunction as measured by a reduction in fractional shortening (FS) [control 54.8±3.0%; AngII 35.3±1.9%; p<0.05]. Minipumps were replaced and mice received either H 2 O, AngII or AngII with Ang-(1-9) (48μg/kg/hr) for a further 2 weeks. Mice receiving Ang-(1-9) in addition to AngII showed a recovery in FS [control 50.5±2.2%; AngII 33.6±1.9%; AngII+Ang-(1-9) 44.0±3.5%; p<0.05]. However, Ang-(1-9) did not affect AngII-induced cardiac hypertrophy [heart weight/tibia length (mg/mm): control 10.6±0.4; AngII 11.6±0.4; AngII+Ang-(1-9) 13.32±0.9], cardiomyocyte size [control 23.2±0.9μm; AngII 26.1±1.0μm; AngII+Ang-(1-9) 28.3±1.2μm] or myocardial fractions of collagen I [control 2.3±0.4%; AngII 6.5±0.9%; AngII+Ang-(1-9) 5.0±0.5%] and collagen III [control 2.0±0.3%; AngII 4.1±0.7%; AngII+Ang-(1-9) 3.0±1.3%]. To determine if Ang-(1-9) directly alters cardiac contractility, isolated rat hearts were Langendorff perfused at a constant heart rate (320 bpm) and intra-ventricular pressure was measured. Perfusion with 1μm Ang-(1-9) for 10min induced a significant and sustained increase in developed pressure [max. response: 105.8% normalised to control; p<0.05]. In contrast, perfusion with 1μm AngII only led to a small transient increase in developed pressure whereas Ang-(1-7) had no effect. These results demonstrate for the first time that Ang-(1-9) reverses chronic AngII-induced cardiac dysfunction and acts directly as a positive inotrope suggesting therapeutic potential in various CVDs.

Abstract P323: Waon Therapy, a Form of Thermal Therapy, Reduces Oxidative Stress Systemically and Inhibits the Progression of Cardiac Dysfunction in TO-2 Cardiomyopathic Hamsters with Heart Failure

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Yoshiyuki Ikeda ◽  
Masaaki Miyata ◽  
Yuichi Akasaki ◽  
Takahiro Miyauchi ◽  
Yuko Furusho ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Cardiac Dysfunction ◽  
Therapy Group ◽  
Left Ventricular ◽  
Thermal Therapy ◽  
Control Group ◽  
Vascular Endothelial ◽  
Cardiac Apoptosis ◽  
Cardiomyopathic Hamsters

Background: Oxidative stress is one of the most crucial factors that develop chronic heart failure (CHF), leading to cardiac apoptosis and fibrosis and vascular endothelial dysfunction. We have reported that Waon therapy, which is a form of thermal therapy using a far infrared-ray dry sauna at 60 degrees centigrade, improves cardiac and vascular endothelial functions and prognosis in patients with CHF. The aim of this study is to investigate whether Waon therapy reduces oxidative stress and prevents from developing cardiac dysfunction in CHF. Methods: Thirty-week old male TO-2 cardiomyopathic hamsters with CHF were divided into Waon therapy or control group. Waon therapy group underwent Waon therapy daily for 4 weeks. Control hamsters did not take any treatment. We examined the amounts of reactive oxygen species of serum, hearts and aortas using ELISA and immunohistochemistry. We measured left ventricular % fractional shortening (LV%FS), and performed TUNEL and Azan staining of hearts to assess cardiac function, apoptosis and fibrosis, respectively. Anti-oxidants and apoptotic and angiogenetic factors were assessed by Western blot. All examinations were performed after 4 weeks of treatment. Results: Four-week Waon therapy significantly decreased oxidative stress of serum, hearts and aortas compared to those of controls. Waon therapy significantly increased LV%FS and decreased cardiac apoptosis and fibrosis (LV%FS, Waon therapy: 23.3±4.3 vs. control: 16.5±4.2%, P<0.01, TUNEL positive nuclei, 22.0±2.6 vs. 49.3±7.2%, P<0.01, % fibrosis, 20.6±5.3 vs. 47.6±4.8%, P<0.01). Waon therapy significantly increased the expressions of manganese superoxide dismutase, heat shock protein 27 (HSP27) and HSP32 of hearts and aortas, which negatively modulate oxidative stress, compared to those of controls. Waon therapy significantly increased endothelial nitric oxide synthase and decreased plasminogen activator inhibitor-1 of aortas. In addition, Waon therapy significantly decreased Bax, cleaved caspase 3 and cytochrome c and increased Bcl-2 and hypoxia-inducible factor-1α of the failing hearts. Conclusions: Waon therapy reduces oxidative stress systemically and inhibits the progression of cardiac dysfuntion in TO-2 cardiomyopathic hamsters.

scholarly journals Cardioprotective Effects of Metformin and Vildagliptin in Adult Rats with Insulin Resistance Induced by a High-Fat Diet

Endocrinology ◽  
2012 ◽  
Vol 153 (8) ◽  
pp. 3878-3885 ◽  
Author(s):  
Nattayaporn Apaijai ◽  
Hiranya Pintana ◽  
Siriporn C. Chattipakorn ◽  
Nipon Chattipakorn
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Body Weight ◽  
Mitochondrial Dysfunction ◽  
Cardiac Dysfunction ◽  
High Fat Diet ◽  
Plasma Insulin ◽  
High Fat ◽  
Antidiabetic Drug ◽  
Sympathovagal Imbalance

Insulin resistance has been shown to be associated with cardiac sympathovagal imbalance, myocardial dysfunction, and cardiac mitochondrial dysfunction. Whereas metformin is a widely used antidiabetic drug to improve insulin resistance, vildagliptin is a novel oral antidiabetic drug in a group of dipeptidyl peptidase-4 inhibitors in which its cardiac effect is unclear. This study aimed to determine the cardiovascular effects of metformin and vildagliptin in rats with insulin resistance induced by high-fat diet. Male Wistar rats were fed with either a normal diet or high-fat diet (n =24 each) for 12 wk. Rats in each group were divided into three subgroups to receive the vehicle, metformin (30 mg/kg, twice daily), or vildagliptin (3 mg/kg, once daily) for another 21 d. Heart rate variability (HRV), cardiac function, and cardiac mitochondrial function were determined and compared among these treatment groups. Rats exposed to a high-fat diet developed increased body weight, visceral fat, plasma insulin, cholesterol, oxidative stress, depressed HRV, and cardiac mitochondrial dysfunction. Metformin and vildagliptin did not alter body weight and plasma glucose levels but decreased the plasma insulin, total cholesterol, and oxidative stress levels. Although both metformin and vildagliptin attenuated the depressed HRV, cardiac dysfunction, and cardiac mitochondrial dysfunction, vildagliptin was more effective in this prevention. Furthermore, only vildagliptin prevented cardiac mitochondrial membrane depolarization caused by consumption of a high-fat diet. We concluded that vildagliptin is more effective in preventing cardiac sympathovagal imbalance and cardiac dysfunction, as well as cardiac mitochondrial dysfunction, than metformin in rats with insulin resistance induced by high-fat diet.

scholarly journals Role of Oxidative Stress in Thyroid Hormone-Induced Cardiomyocyte Hypertrophy and Associated Cardiac Dysfunction: An Undisclosed Story

2015 ◽  
Vol 2015 ◽  
pp. 1-16 ◽  
Author(s):  
Mohammad T. Elnakish ◽  
Amany A. E. Ahmed ◽  
Peter J. Mohler ◽  
Paul M. L. Janssen
Keyword(s):  
Oxidative Stress ◽  
Thyroid Hormone ◽  
Cardiac Hypertrophy ◽  
Cardiac Dysfunction ◽  
Ventricular Hypertrophy ◽  
Cardiomyocyte Hypertrophy ◽  
Oxygen Species ◽  
Whole Heart ◽  
Shed Light

Cardiac hypertrophy is the most documented cardiomyopathy following hyperthyroidism in experimental animals. Thyroid hormone-induced cardiac hypertrophy is described as a relative ventricular hypertrophy that encompasses the whole heart and is linked with contractile abnormalities in both right and left ventricles. The increase in oxidative stress that takes place in experimental hyperthyroidism proposes that reactive oxygen species are key players in the cardiomyopathy frequently reported in this endocrine disorder. The goal of this review is to shed light on the effects of thyroid hormones on the development of oxidative stress in the heart along with the subsequent cellular and molecular changes. In particular, we will review the role of thyroid hormone-induced oxidative stress in the development of cardiomyocyte hypertrophy and associated cardiac dysfunction, as well as the potential effectiveness of antioxidant treatments in attenuating these hyperthyroidism-induced abnormalities in experimental animal models.

scholarly journals The Programming of Cardiac Hypertrophy in the Offspring by Maternal Obesity Is Associated with Hyperinsulinemia, AKT, ERK, and mTOR Activation

Endocrinology ◽  
2012 ◽  
Vol 153 (12) ◽  
pp. 5961-5971 ◽  
Author(s):  
Denise S. Fernandez-Twinn ◽  
Heather L. Blackmore ◽  
Lee Siggens ◽  
Dino A. Giussani ◽  
Christine M. Cross ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Body Weight ◽  
Cardiac Hypertrophy ◽  
Maternal Obesity ◽  
Mammalian Target Of Rapamycin ◽  
Left Ventricular ◽  
Target Of Rapamycin ◽  
Heart Weight ◽  
Cardiac Phenotype ◽  
Pregnancy And Lactation

Abstract Human and animal studies suggest that suboptimal early nutrition during critical developmental periods impacts long-term health. For example, maternal overnutrition during pregnancy and lactation in mice programs insulin resistance, obesity, and endothelial dysfunction in the offspring. Here we investigated the effects of diet-induced maternal obesity on the offspring cardiac phenotype and explored potential underlying molecular mechanisms. Dams fed the obesogenic diet were heavier (P &lt; 0.01) and fatter (P &lt; 0.0001) than controls throughout pregnancy and lactation. There was no effect of maternal obesity on offspring body weight or body composition up to 8 wk of age. However, maternal obesity resulted in increased offspring cardiac mass (P &lt; 0.05), increased heart-body weight (P &lt; 0.01), heart weight-tibia length (P &lt; 0.05), increased left ventricular free wall thickness and area (P &lt; 0.01 and P &lt; 0.05, respectively), and increased myocyte width (P &lt; 0.001). Consistent with these structural changes, the expression of molecular markers of cardiac hypertrophy were also increased [Nppb(BNP), Myh7-Myh6(βMHC-αMHC) (both P &lt; 0.05) and mir-133a (P &lt; 0.01)]. Offspring were hyperinsulinemic and displayed increased insulin action through AKT (P &lt; 0.01), ERK (P &lt; 0.05), and mammalian target of rapamycin (P &lt; 0.05). p38MAPK phosphorylation was also increased (P &lt; 0.05), suggesting pathological remodeling. Increased Ncf2(p67phox) expression (P &lt; 0.05) and impaired manganese superoxide dismutase levels (P &lt; 0.01) suggested oxidative stress, which was consistent with an increase in levels of 4-hydroxy-2-trans-nonenal (a measure of lipid peroxidation). We propose that maternal diet-induced obesity leads to offspring cardiac hypertrophy, which is independent of offspring obesity but is associated with hyperinsulinemia-induced activation of AKT, mammalian target of rapamycin, ERK, and oxidative stress.

scholarly journals Cardiac Dysfunction in a Mouse Vascular Dementia Model of Bilateral Common Carotid Artery Stenosis

2021 ◽  
Vol 8 ◽  
Author(s):  
Lulu An ◽  
Michael Chopp ◽  
Alex Zacharek ◽  
Yi Shen ◽  
Zhili Chen ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cognitive Function ◽  
Carotid Artery ◽  
Vascular Dementia ◽  
Common Carotid Artery ◽  
Cardiac Dysfunction ◽  
Carotid Artery Stenosis ◽  
Artery Stenosis ◽  
Heart Weight ◽  
Bilateral Common Carotid Artery

Background: Cardiac function is associated with cognitive function. Previously, we found that stroke and traumatic brain injury evoke cardiac dysfunction in mice. In this study, we investigate whether bilateral common carotid artery stenosis (BCAS), a model that induces vascular dementia (VaD) in mice, induces cardiac dysfunction.Methods: Late-adult (6–8 months) C57BL/6J mice were subjected to sham surgery (n = 6) or BCAS (n = 8). BCAS was performed by applying microcoils (0.16 mm internal diameter) around both common carotid arteries. Cerebral blood flow and cognitive function tests were performed 21–28 days post-BCAS. Echocardiography was conducted in conscious mice 29 days after BCAS. Mice were sacrificed 30 days after BCAS. Heart tissues were isolated for immunohistochemical evaluation and real-time PCR assay.Results: Compared to sham mice, BCAS in mice significantly induced cerebral hypoperfusion and cognitive dysfunction, increased cardiac hypertrophy, as indicated by the increased heart weight and the ratio of heart weight/body weight, and induced cardiac dysfunction and left ventricular (LV) enlargement, indicated by a decreased LV ejection fraction (LVEF) and LV fractional shortening (LVFS), increased LV dimension (LVD), and increased LV mass. Cognitive deficits significantly correlated with cardiac deficits. BCAS mice also exhibited significantly increased cardiac fibrosis, increased oxidative stress, as indicated by 4-hydroxynonenal and NADPH oxidase-2, increased leukocyte and macrophage infiltration into the heart, and increased cardiac interleukin-6 and thrombin gene expression.Conclusions: BCAS in mice without primary cardiac disease provokes cardiac dysfunction, which, in part, may be mediated by increased inflammation and oxidative stress.

scholarly journals Quercetin Reverses Cardiac Systolic Dysfunction in Mice Fed with a High-Fat Diet: Role of Angiogenesis

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Shasha Yu ◽  
Seo Rin Kim ◽  
Kai Jiang ◽  
Mikolaj Ogrodnik ◽  
Xiang Y. Zhu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cardiac Fibrosis ◽  
Left Ventricular ◽  
Fat Deposition ◽  
Heart Weight ◽  
Cardiomyocyte Hypertrophy ◽  
High Fat ◽  
Myocardial Oxidative Stress ◽  
Cardioprotective Effects

Global consumption of high-fat diets (HFD) is associated with an increased incidence of cardiometabolic syndrome and cardiac injury, warranting identification of cardioprotective strategies. Cardioprotective effects of quercetin (Q) have mostly been evaluated in ischemic heart disease models and attributed to senolysis. We hypothesized that Q could alleviate murine cardiac damage caused by HFD by restoring the myocardial microcirculation. C57BL/6J mice were fed standard chow or HFD for 6 months and then treated with Q (50 mg/kg) or vehicle 5-day biweekly for 10 additional weeks. Left ventricular (LV) cardiac function was studied in vivo using magnetic resonance imaging, and intramyocardial fat deposition, microvascular density, oxidative stress, and senescence were analyzed ex vivo. Additionally, direct angiogenic effects of Q were studied in vitro in HUVECs. HFD increased body weight, heart weight, total cholesterol, and triglyceride levels, whereas Q normalized heart weight and triglycerides. LV ejection fraction was lower in HFD vs. control mice ( 56.20 ± 15.8 % vs. 73.38 ± 5.04 % , respectively, P < 0.05 ), but improved in HFD + Q mice ( 67.42 ± 7.50 % , P < 0.05 , vs. HFD). Q also prevented cardiac fat accumulation and reduced HFD-induced cardiac fibrosis, cardiomyocyte hypertrophy, oxidative stress, and vascular rarefaction. Cardiac senescence was not observed in any group. In vitro, ox-LDL reduced HUVEC tube formation activity, which Q effectively improved. Quercetin may directly induce angiogenesis and decrease myocardial oxidative stress, which might account for its cardioprotective effects in the murine HFD-fed murine heart independently from senolytic activity. Furthermore, its beneficial effects might be partly attributed to a decrease in plasma triglycerides and intramyocardial fat deposition.

scholarly journals Combination ART-Induced Oxidative/Nitrosative Stress, Neurogenic Inflammation and Cardiac Dysfunction in HIV-1 Transgenic (Tg) Rats: Protection by Mg

2018 ◽  
Vol 19 (8) ◽  
pp. 2409 ◽  
Author(s):  
I. Tong Mak ◽  
Joanna J. Chmielinska ◽  
Christopher F. Spurney ◽  
William B. Weglicki ◽  
Jay H. Kramer
Keyword(s):  
Oxidative Stress ◽  
Substance P ◽  
Cardiac Dysfunction ◽  
Neurogenic Inflammation ◽  
Nitrosative Stress ◽  
Contractile Function ◽  
Stress Injury ◽  
Chronic Effects ◽  
Neutrophil Superoxide ◽  
Hiv 1

Chronic effects of a combination antiretroviral therapy (cART = tenofovir/emtricitatine + atazanavir/ritonavir) on systemic and cardiac oxidative stress/injury in HIV-1 transgenic (Tg) rats and protection by Mg-supplementation were assessed. cART (low doses) elicited no significant effects in normal rats, but induced time-dependent oxidative/nitrosative stresses: 2.64-fold increased plasma 8-isoprostane, 2.0-fold higher RBC oxidized glutathione (GSSG), 3.2-fold increased plasma 3-nitrotyrosine (NT), and 3-fold elevated basal neutrophil superoxide activity in Tg rats. Increased NT staining occurred within cART-treated HIV-Tg hearts, and significant decreases in cardiac systolic and diastolic contractile function occurred at 12 and 18 weeks. HIV-1 expression alone caused modest levels of oxidative stress and cardiac dysfunction. Significantly, cART caused up to 24% decreases in circulating Mg in HIV-1-Tg rats, associated with elevated renal NT staining, increased creatinine and urea levels, and elevated plasma substance P levels. Strikingly, Mg-supplementation (6-fold) suppressed all oxidative/nitrosative stress indices in the blood, heart and kidney and substantially attenuated contractile dysfunction (>75%) of cART-treated Tg rats. In conclusion, cART caused significant renal and cardiac oxidative/nitrosative stress/injury in Tg-rats, leading to renal Mg wasting and hypomagnesemia, triggering substance P-dependent neurogenic inflammation and cardiac dysfunction. These events were effectively attenuated by Mg-supplementation likely due to its substance P-suppressing and Mg’s intrinsic anti-peroxidative/anti-calcium properties.

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