Abstract 12808: Mechanism of Chronic Ranolazine Caused Regression of Cardiac Dysfunction in a Murine of Diabetic Cardiomyopathy: Beneficial Effects on Cardiomyocyte Contractile Function, [Ca 2+ ] i Regulation and Beta-Adrenergic Modulation

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Xiaoqiang Sun ◽  
Jing Cao ◽  
Heng-Jie Cheng ◽  
Yixi Liu ◽  
Zhe Chen ◽  
...  
Keyword(s):  
Diabetic Cardiomyopathy ◽  
Contractile Function ◽  
Cell Contractility ◽  
Beneficial Effects ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
Therapeutic Choice ◽  
Adrenergic Modulation ◽  
Myocyte Function ◽  
Myocyte Contractility

Background: Diabetic cardiomyopathy (DCM) increases the risk of heart failure. As yet, no effective therapeutic strategies exist. Recent evidence indicates that intracellular Na + concentration ([Na + ] i ) is augmented in the myocytes from diabetic hearts, where it causes oxidative stress, augments the sarcoplasmic reticulum Ca 2+ leak and contributes to electrical, structural and functional remodeling. Ranolazine (RAN), inhibiting persistent or late inward Na + current has been proposed to be a therapeutic choice for DCM. However, the role and mechanism of chronic RAN in DCM are unclear. We assessed the hypothesis that RAN improves myocyte function, [Ca 2+ ] i regulation, and β-adrenergic receptor (AR) signaling effectiveness, thus limiting DCM. Methods: We compared LV myocyte function, [Ca 2+ ] i transient ([Ca 2+ ] iT ) and responses to the stimulation of β-AR in 3 groups wild-type (WT) female mice over 10 weeks (W):1) DM (n=8), 10 W after receiving streptozotocin (STZ, 200 mg/kg, ip); 2) DM/RAN (n=6), 6 W after STZ, RAN (10 -5 M/kg/day, mini-pump) was initiated and was given for 4 W; and 3) Sham controls (C) (n=8). Results: Versus control, STZ-treated WT mice had DM with significantly elevated blood glucose levels (410 vs 128mg/dl) followed by LV myocyte dysfunction with decreases in myocyte contractility (dL/dt max ) (75.0 vs 140.1 μm/s), relengthening (dR/dt max ) (62.5 vs 116.6 μm/s) and [Ca 2+ ] iT (0.15 vs 0.22). In DM myocytes, the ability of β-AR agonist, isoproterenol (ISO, 10 -8 M) to increase cell contractility was blunted. Versus control, in DM myocytes, ISO-induced increases in dL/dt max (31% vs 60%), dR/dt max (23% vs 50%) and [Ca 2+ ] iT (15% vs 30%) were significantly reduced. By contrary, versus DM alone, DM/RAN myocytes showed normal basal cell contraction (137.8 μm/s), relaxation (117.2 μm/s) and [Ca 2+ ] iT (0.22) with preserved ISO-stimulated positive inotropic effect. Compared control, in DM/RAN, ISO caused similar increases in dL/dt max (62% vs 60%), dR/dt max (52% vs 50%) and [Ca 2+ ] iT (32% vs 30%). Conclusion: Chronic ranolazine leads to the preservation of myocyte function, [Ca 2+ ] iT and β-AR responsiveness in DCM. Thus, antagonizing myocyte [Na + ] i dysregulation might provide a new therapeutic strategy for DM-related decline in myocardial function.

Abstract 13035: Beta3-Adrenergic-Receptor-Deficient Mice Protected From Diabetic Cardiomyopathy in Type 2 Diabetic Murine Model: Beneficial Effects on Cardiomyocyte Contractile Function, [Ca 2+ ] i Regulation and Beta-Adrenergic Modulation

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Xiaoqiang Sun ◽  
Jing Cao ◽  
Heng-Jie Cheng ◽  
Yixi Liu ◽  
Zhe Chen ◽  
...  
Keyword(s):  
Diabetic Cardiomyopathy ◽  
Adrenergic Receptor ◽  
Contractile Function ◽  
Progressive Decline ◽  
Beneficial Effects ◽  
Adrenergic Modulation ◽  
Myocyte Function ◽  
Mean Blood Glucose ◽  
Deficient Mice

Background: Diabetic cardiomyopathy (DCM) is the main cause of increased mortality in Diabetes mellitus (DM). There are no effective therapeutic strategies. Recently, we found that DM is associated with the upregulation of β 3 adrenergic receptor (AR) mediated cardiac inhibitory pathway. This suggests cardiac β 3 -AR activation may contribute to DCM progression and be a therapeutic target. We hypothesize that upregulation of β 3 -AR is maladaptive, and DM-caused progressive decline in cardiac function and β-adrenergic reserve will be prevented in β 3 -AR knockout (β 3 KO) mice. Methods: Studies were conducted in female mice of 2 Vehicle controls groups (n=8/group) of wild-type (CWT) and Cβ 3 KO, and 2 Type 2 DM (T2) of T2WT (n=8) and T2β 3 KO (n=6).T2 was induced by fed high-fat diet (HFD) for 14 weeks (W), but after HFD for 4 W receiving streptozotocin (STZ, 40 mg/kg/day, i.p. for 5 days). We compared LV myocyte contractile and [Ca 2+ ] iT responses to β-AR subtype stimulation by random exposure of myocytes to the superfusion of isoproterenol (ISO,10 -8 M) or a selective β 1 -, or β 3 -agonist, Norepinephrine (NE, 10 -7 M), and BRL-37,344 (BRL, 10 -8 M), respectively. Results: Mice received HFD plus STZ developed T2DM with elevated mean blood glucose from 128 mg/dl of control to 388 mg/dl and 382 mg/dl in T2WT and T2β 3 KO, respectively. However only T2WT mice developed DCM followed by significant decreases in myocyte contraction (dL/dt max , T2WT: 74.8 vs CWT:140.1 μm/s), relaxation (dR/dt max , 58.0 vs 117.9 μm/s) and [Ca 2+ ] iT (0.16 vs 0.22). ISO-stimulated increases in dL/dt max (37% vs 58%), dR/dt max (30% vs 53%), and [Ca 2+ ] iT (19% vs 30%) were attenuated accompanied by a diminished NE-caused increase in dL/dt max (28% vs 41%), but enhanced BRL-induced decrease in dL/dt max (29% vs 15%). By contrary, T2β 3 KO showed normal basal dL/dt max (137.6 μm/s), dR/dt max (111.4 μm/s) and [Ca 2+ ] iT (0.22). Importantly, T2β 3 KO myocytes showed preserved ISO-stimulated increases in dL/dt max (60%), dR/dt max (51%) and [Ca 2+ ] iT (32%) and restored normal dL/dt max responses to NE (41%). Conclusions: β 3 KO prevents T2DM-caused contrast changes in β 1 - and β 3 -AR-stimulated cardiac inotropic actions and leading to the preservation of normal myocyte function, [Ca 2+ ] iT , and β-AR responsiveness in DCM.

Abstract 13045: Chronic Beta3-Adrenergic Receptor Antagonist Therapy Rescues Diabetic Cardiomyopathy in a Mouse Model With Type 2 Diabetes: Insights into Cellular Mechanism

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Jing Cao ◽  
Xiaoqiang Sun ◽  
Heng Jie Cheng ◽  
Yixi Liu ◽  
Dalane Kitzman ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Mouse Model ◽  
Diabetic Cardiomyopathy ◽  
Adrenergic Receptor ◽  
Effective Prevention ◽  
Glucose Levels ◽  
Wild Type Female ◽  
Myocyte Function ◽  
Myocyte Contractility

Background: Diabetic cardiomyopathy (DCM) leads to progressive decline in cardiac function, increasing the risk for heart failure. There are no known effective prevention approaches or therapeutic strategies. Recent evidence in diabetes mellitus (DM) human and animal hearts suggests that the up-regulation of β 3 -adrenergic receptor (AR)-mediated inhibitory pathway may be responsible for the progression of DCM. However, its precise role is still being debated. We hypothesize that β 3 -AR antagonists (β 3 -ANT) may rescue the detrimental effects of β 3 -AR activation, improve cardiomyocyte function, and preserve normal β-AR regulation, leading to the regression of DCM. Methods: We compared LV myocyte function, [Ca 2+ ] i transient ([Ca 2+ ] iT ) at baseline and responses to β-AR simulation with isoproterenol (ISO,10 -8 M) in 3 groups wild-type female mice over 14 weeks (W):1) Type 2 DM ( T2 ) (n=9), 14 W fed high-fat diet (HFD), but after HFD for 4 W receiving streptozotocin (STZ, 40 mg/kg/day, i.p. 5 days); 2) T2/β 3 -ANT (n=7), T2 mice at 10 W received L-748,337, a selective β 3 -ANT (10 -7 M/kg/day, mini-pump) for 4 W; and 3) Vehicle controls (C) (n=9). Results: Versus C, T2DM was induced in mice received HFD and low dose STZ with significantly elevated blood glucose levels (T2: 388, T2/β 3 -ANT: 369 vs C: 128 mg/dl). In T2, LV myocyte basal function and [Ca 2+ ] iT regulation were impaired measured as significantly decreased myocyte contractility (dL/dt max ) (76.8 vs 135.2 μm/s), relengthening (dR/dt max ) (62.1 vs 113.8 μ m/s) and [Ca 2+ ] iT (0.16 vs 0.21). Furthermore, versus C, in T2 myocytes, ISO-induced increases in dL/dt max (T2: 40% vs C: 58%), dR/dt max (35% vs 54%) and [Ca 2+ ] iT (19% vs 30%) were significantly reduced. By contrary, versus T2, T2/β 3 -ANT myocytes showed normal basal cell contraction (127.8 μm/s), relaxation (109.4 μm/s) and [Ca 2+ ] iT (0.21) with preserved ISO-stimulated positive inotropic effect. Versus C, in T2/β 3 -ANT, ISO caused similar increases in dL/dt max (57%), dR/dt max (52%) and [Ca 2+ ] iT (30%). Conclusion: Chronic β 3 -ANT leads to the preservation of LV myocyte function, [Ca 2+ ] iT , and β-AR responsiveness in a mouse model of type 2 diabetes. Thus, antagonizing β 3 -AR might provide a new therapeutic strategy for DM-related decline in myocardial function.

scholarly journals Effects of Apocynin on Heart Muscle Oxidative Stress of Rats with Experimental Diabetes: Implications for Mitochondria

Antioxidants ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 335
Author(s):  
Estefanía Bravo-Sánchez ◽  
Donovan Peña-Montes ◽  
Sarai Sánchez-Duarte ◽  
Alfredo Saavedra-Molina ◽  
Elizabeth Sánchez-Duarte ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Insulin Sensitivity ◽  
Cardiac Tissue ◽  
Diabetic Rats ◽  
Oxidase Inhibitor ◽  
Beneficial Effects ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
Transport Chain ◽  
Male Wistar Rats

Diabetes mellitus (DM) constitutes one of the public health problems today. It is characterized by hyperglycemia through a defect in the β-cells function and/or decreased insulin sensitivity. Apocynin has been tasted acting directly as an NADPH oxidase inhibitor and reactive oxygen species (ROS) scavenger, exhibiting beneficial effects against diabetic complications. Hence, the present study’s goal was to dissect the possible mechanisms by which apocynin could mediate its cardioprotective effect against DM-induced oxidative stress. Male Wistar rats were assigned into 4 groups: Control (C), control + apocynin (C+A), diabetes (D), diabetes + apocynin (D+A). DM was induced with streptozotocin. Apocynin treatment (3 mg/kg/day) was applied for 5 weeks. Treatment significantly decreased blood glucose levels and insulin resistance in diabetic rats. In cardiac tissue, ROS levels were higher, and catalase enzyme activity was reduced in the D group compared to the C group; the apocynin treatment significantly attenuated these responses. In heart mitochondria, Complexes I and II of the electron transport chain (ETC) were significantly enhanced in the D+A group. Total glutathione, the level of reduced glutathione (GSH) and the GSH/ oxidized glutathione (GSSG) ratio were increased in the D+A group. Superoxide dismutase (SOD) and the glutathione peroxidase (GSH-Px) activities were without change. Apocynin enhances glucose uptake and insulin sensitivity, preserving the antioxidant defense and mitochondrial function.

scholarly journals Leptin contributes to the beneficial effects of insulin treatment in streptozotocin-diabetic male mice

2018 ◽  
Vol 315 (6) ◽  
pp. E1264-E1273
Author(s):  
Ursula H. Neumann ◽  
Michelle M. Kwon ◽  
Robert K. Baker ◽  
Timothy J. Kieffer
Keyword(s):  
Blood Glucose ◽  
Insulin Therapy ◽  
Daily Injection ◽  
Diabetic Mice ◽  
Glucose Lowering ◽  
Beneficial Effects ◽  
Glucose Levels ◽  
Lowering Effect ◽  
Blood Glucose Levels ◽  
Glucose Lowering Effect

It was long thought that the only hormone capable of reversing the catabolic consequences of diabetes was insulin. However, various studies have demonstrated that the adipocyte-derived hormone leptin can robustly lower blood glucose levels in rodent models of insulin-deficient diabetes. In addition, it has been suggested that some of the metabolic manifestations of insulin-deficient diabetes are due to hypoleptinemia as opposed to hypoinsulinemia. Because insulin therapy increases leptin levels, we sought to investigate the contribution of leptin to the beneficial effects of insulin therapy. To do this, we tested insulin therapy in streptozotocin (STZ) diabetic mice that were either on an ob/ ob background or that were given a leptin antagonist to determine if blocking leptin action would blunt the glucose-lowering effects of insulin therapy. We found that STZ diabetic ob/ ob mice have a diminished blood glucose-lowering effect in response to insulin therapy compared with STZ diabetic controls and exhibited more severe weight loss post-STZ injection. In addition, STZ diabetic mice administered a leptin antagonist through daily injection or plasmid expression respond less robustly to insulin therapy as assessed by both fasting blood glucose levels and blood glucose levels during an oral glucose tolerance test. However, leptin antagonism did not prevent the insulin-induced reduction in β-hydroxybutyrate and triglyceride levels. Therefore, we conclude that elevated leptin levels can contribute to the glucose-lowering effect of insulin therapy in insulin-deficient diabetes.

scholarly journals Preventive Effect of Salicylate and Pyridoxamine on Diabetic Nephropathy

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Tarek Kamal Abouzed ◽  
Seiichi Munesue ◽  
Ai Harashima ◽  
Yusuke Masuo ◽  
Yukio Kato ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Blood Glucose ◽  
Macrophage Infiltration ◽  
Gene Expressions ◽  
Beneficial Effects ◽  
Glucose Levels ◽  
Developmental Factors ◽  
Blood Glucose Levels ◽  
Patients With Diabetes ◽  
Long Acting

Objective. Diabetic nephropathy is a life-threatening complication in patients with long-standing diabetes. Hemodynamic, inflammatory, and metabolic factors are considered as developmental factors for diabetic nephropathy. In this study, we evaluated whether pharmacological interventions with salicylate, compared to pyridoxamine, could prevent diabetic nephropathy in mice. Methods. Male mice overexpressing inducible nitric oxide synthase in pancreatic β-cells were employed as a diabetic model. Salicylate (3 g/kg diet) or pyridoxamine (1 g/L drinking water; ~200 mg/kg/day) was given for 16 weeks to assess the development of diabetic nephropathy. Treatment with long-acting insulin (Levemir 2 units/kg twice a day) was used as a control. Results. Although higher blood glucose levels were not significantly affected by pyridoxamine, early to late stage indices of nephropathy were attenuated, including kidney enlargement, albuminuria, and increased serum creatinine, glomerulosclerosis, and inflammatory and profibrotic gene expressions. Salicylate showed beneficial effects on diabetic nephropathy similar to those of pyridoxamine, which include lowering blood glucose levels and inhibiting macrophage infiltration into the kidneys. Attenuation of macrophage infiltration into the kidneys and upregulation of antiglycating enzyme glyoxalase 1 gene expression were found only in the salicylate treatment group. Conclusions. Treatment with salicylate and pyridoxamine could prevent the development of diabetic nephropathy in mice and, therefore, would be a potentially useful therapeutic strategy against kidney problems in patients with diabetes.

scholarly journals The Beneficial Effects of SesaVitaTM on Lipid Profiles and Blood Glucose Levels in Subjects With Prediabetes and Mild-To-Moderate Hyperlipidemia in India

2013 ◽  
Vol 2 (5) ◽  
pp. 104 ◽  
Author(s):  
H. N. Shivaprasad ◽  
M. Bhanumathy ◽  
Ceyhun Tamer ◽  
G. Sushma ◽  
K. R. Raveendra ◽  
...  
Keyword(s):  
Blood Glucose ◽  
Lipid Profile ◽  
Lifestyle Changes ◽  
Secondary Outcome ◽  
Oral Glucose ◽  
Double Blind Study ◽  
Beneficial Effects ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
Normal Ranges

<p>Individuals suffering from Type 2 diabetes develop prediabetes before progression of diabetes. In case of prediabetes people, the blood glucose levels are higher than normal but not sufficient to be diagnosed as diabetes. On the basis of existing reports on Sesame extract, SesaVita<sup>TM</sup> which is an herbal food supplement containing Sesame seeds (<em>Sesamum indicum</em> L.) extract may provide an option for management of prediabetes. The objective of this study was to determine the beneficial effects of SesaVita<sup>TM</sup> in prediabetes and mild to moderate hyperlipidemia subjects. This randomized, placebo-controlled, double-blind study comprised of 13 female and 07 male patients with prediabetes and mild to moderate hyperlipidemia, aged between 18 and 65 years. Twenty subjects were randomized to receive SesaVita<sup>TM</sup> (500 mg/day) or placebo along with therapeutic lifestyle changes for 6 weeks. The primary outcome was the measure of efficacy in terms of change in serum lipid profile and glycaemic levels on week 3 and 6. Secondary outcome measures include safety and tolerability evaluated by physical examination and clinical laboratory evaluations. Improvements in lipid profile and glycaemic levels were observed in SesaVita<sup>TM</sup> treated group when compared with placebo and baseline. A statistical significant reduction was observed in low density lipoprotein cholesterol (LDL-C), total cholesterol (TC), oral glucose tolerance test (OGTT) and fasting blood sugar (FBS) levels during week 3 and 6 when treated with SesaVita<sup>TM</sup> extract.<em> </em>No adverse events occurred and all safety parameters were within normal ranges during the study. This study revealed that the treatment with SesaVita<sup>TM</sup> was safe and well tolerated;<em> </em>may be beneficial in the management of prediabetes and mild-to-moderate hyperlipidemia.</p>

scholarly journals Modulation of the JNK Pathway in Liver Affects Insulin Resistance Status

2004 ◽  
Vol 279 (44) ◽  
pp. 45803-45809 ◽  
Author(s):  
Yoshihisa Nakatani ◽  
Hideaki Kaneto ◽  
Dan Kawamori ◽  
Masahiro Hatazaki ◽  
Takeshi Miyatsuka ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Glucose Tolerance ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Dominant Negative ◽  
Diabetic Mice ◽  
Jnk Pathway ◽  
Beneficial Effects ◽  
Glucose Levels ◽  
Blood Glucose Levels

The c-Jun N-terminal kinase (JNK) pathway is known to be activated under diabetic conditions and to possibly be involved in the progression of insulin resistance. In this study, we examined the effects of modulation of the JNK pathway in liver on insulin resistance and glucose tolerance. Overexpression of dominant-negative type JNK in the liver of obese diabetic mice dramatically improved insulin resistance and markedly decreased blood glucose levels. Conversely, expression of wild type JNK in the liver of normal mice decreased insulin sensitivity. The phosphorylation state of crucial molecules for insulin signaling was altered upon modification of the JNK pathway. Furthermore, suppression of the JNK pathway resulted in a dramatic decrease in the expression levels of the key gluconeogenic enzymes, and endogenous hepatic glucose production was also greatly reduced. Similar effects were observed in high fat, high sucrose diet-induced diabetic mice. Taken together, these findings suggest that suppression of the JNK pathway in liver exerts greatly beneficial effects on insulin resistance status and glucose tolerance in both genetic and dietary models of diabetes.

scholarly journals Health benefits of barley for diabetes

2020 ◽  
Vol 12 ◽  
Author(s):  
Emmanuel Idehen ◽  
Weixin Wang ◽  
Shengmin Sang
Keyword(s):  
Short Chain Fatty Acids ◽  
The United States ◽  
Glycemic Response ◽  
Soluble Fiber ◽  
Beta Glucan ◽  
Beneficial Effects ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
Health Promoting ◽  
Underlying Mechanisms

Type 2 diabetes (T2D) is one of the most prevalent metabolic disorders in the United States. Increased blood glucose levels and improper crucial metabolism ensuing from insulin action, insulin secretion defect, or both are characteristics of this disease. The risk of developing T2D is associated with many factors, including obesity, race, inactivity, and genetics. Increased whole-grain (WG) consumption has been reported to lower the risk of obesity and T2D. Among WGs, barley shows a comparative advantage in its fiber content, especially the soluble fiber, beta-glucan (β-glucan), an active component credited for this benefit. Barley also contains important phytochemicals, mostly intertwined with its fiber, reported to also offer glycemic response benefits. The mechanism by which barley exerts these changes in glycemic response is not entirely understood. However, the physical properties of barley fiber, the function of microbial metabolites of fiber, short chain fatty acids, and the beneficial effects of its phytochemicals through multiple pathways have all been reported as the potential mechanisms for its antidiabetic effects. This review summarizes recent studies concerning the health-promoting benefit of barley in preventing and moderating the risk factors associated with diabetes and the potential underlying mechanisms.

scholarly journals Beneficial Effects of Aminoguanidine on Skin Flap Survival in Diabetic Rats

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Ayse Ozturk ◽  
Cemal Fırat ◽  
Hakan Parlakpınar ◽  
Aysun Bay-Karabulut ◽  
Hale Kirimlioglu ◽  
...  
Keyword(s):  
Skin Flap ◽  
Diabetic Rats ◽  
Random Pattern ◽  
Protective Effects ◽  
Sod Activity ◽  
Beneficial Effects ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
Flap Viability ◽  
Skin Flap Survival

Random flaps in DM patients have poor reliability for wound coverage, and flap loss remains a complex challenge. The protective effects of aminoguanidine (AG) administration on the survival of dorsal random flaps and oxidative stress were studied in diabetic rats. Two months after the onset of DM, dorsal McFarlane flaps were raised. Forty rats were divided into four groups: (1) control, (2) AG, (3) DM, and (4) DM + AG groups. Flap viability, determined with the planimetric method, and free-radical measurements were investigated. In addition, HbA1c and blood glucose levels, body weight measurements, and histopathological examinations were evaluated. The mean flap necrotic areas (%) in Groups I to IV were 50.9 ± 13.0, 32.9 ± 12.5, 65.2 ± 11.5, and 43.5 ± 14.7, respectively. The malondialdehyde (MDA) and nitric oxide (NO) levels were higher in the DM group than in the nondiabetic group, while the reduced glutathione (GSH) levels and superoxide dismutase (SOD) activity were reduced as a result of flap injury. In the diabetic and nondiabetic groups, AG administration significantly reduced the MDA and NO levels and significantly increased GSH content and SOD enzyme activity. We concluded that AG plays an important role in preventing random pattern flap necrosis.

Abstract 035: Mechanism of Chronic CaMKII Inhibition-Caused Regression of Heart Failure: Beneficial Effects on Neurohormonal Activation, Left Ventricular and Cardiomyocyte Contractile Function, [Ca 2 +]i Regulation and Beta-Adrenergic Modulation

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Che Ping Cheng ◽  
Qun Shao ◽  
Heng-Jie Cheng ◽  
Michael F Callahan
Keyword(s):  
Heart Failure ◽  
Contractile Function ◽  
Left Ventricular ◽  
Functional Responses ◽  
Beneficial Effects ◽  
Adrenergic Modulation ◽  
Dependent Protein ◽  
System Activation ◽  
Contraction And Relaxation ◽  
To Receive

Background: Recent evidence indicates that Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) is upregulated in heart failure (HF), contributing to electric, structural and functional remodeling. CaMKII has been proposed to be a therapeutic target for HF. However, the role and mechanism of chronic CaMKII inhibition (I) in HF is unclear. We assessed the hypothesis that CaMKII I improves cardiomyocyte function, [Ca 2+ ] i regulation, and β-adrenergic reserve, thus limiting HF progression. Methods: We compared left ventricular (LV) and myocyte functional responses and plasma levels of norepinephrine (NE) over a period of 16 weeks (W) in 6 control (C) and 14 rats with HF induced by isoproterenol (ISO) (170 mg/kg sq for 2 days). After ISO for 12 weeks, HF animals were assigned to receive 4 W treatment with: placebo (saline) (n=6), KN-93 (70 µg/kg/day sq via mini pump) (n=6), or KN-92 (70 µg/kg/day sq via pump) (n=2), respectively. Results: Compared with C, ISO-treated rats had HF onset at 4 W after ISO and progressed to severe HF at 16 W with increased plasma NE (1398 vs 342 pg/ml), decreased ejection fraction (EF, 37% vs 62%) and LV contractility (E ES , 0.8 vs 1.3 mmHg/μl). LV time constant of relaxation (τ) (17.8 vs 10.6 ms) increased, accompanied with significant reductions in cell contraction (dL/dt max , 78 vs 151 μm/s), relaxation (dR/dt max , 59 vs 114 μm/s) and [Ca 2+ ] i transient ([Ca 2+ ] iT ) (0.18 vs 0.28). HF myocyte response to β-AR stimulation (ISO, 10 -8 M) was attenuated with significantly less increases in dL/dt max (34% vs 79%) and [Ca 2+ ] iT (19% vs 36%). The LV and myocyte dysfunction persisted in KN-92-treated HF group. In contrast, treatment with KN-93 significantly increased E ES (1.2 mmHg/μl) and EF (60%), decreased τ (12.1 ms) and corrected the elevation of plasma NE (319 pg/ml). Importantly, basal myocyte contraction (dL/dt max ,147 μm/s), relaxation (dR/dt max ,107 μm/s), and [Ca 2+ ] iT (0.25) improved. ISO-induced increase in dL/dt max (71%) and [Ca 2+ ] iT (32%) were augmented and close to normal control levels. Conclusion: Chronic CaMKII I prevents HF-induced sympathetic nervous system activation and improves LV and cardiomyocyte basal and β-AR stimulated contraction and relaxation, thus playing a salutary role at later stages of HF.

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