scholarly journals Functional and Molecular Characterisation of Heart Failure Progression in Mice and the Role of Myosin Regulatory Light Chains in the Recovery of Cardiac Muscle Function

2021 ◽  
Vol 23 (1) ◽  
pp. 88
Author(s):  
Kasturi Markandran ◽  
Haiyang Yu ◽  
Weihua Song ◽  
Do Thuy Uyen Ha Lam ◽  
Mufeeda Madathummal ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Muscle ◽  
Protein Modification ◽  
Troponin I ◽  
Isometric Force ◽  
Left Ventricular ◽  
Light Chains ◽  
Regulatory Light Chains ◽  
Sarcomeric Protein

Heart failure (HF) as a result of myocardial infarction (MI) is a major cause of fatality worldwide. However, the cause of cardiac dysfunction succeeding MI has not been elucidated at a sarcomeric level. Thus, studying the alterations within the sarcomere is necessary to gain insights on the fundamental mechansims leading to HF and potentially uncover appropriate therapeutic targets. Since existing research portrays regulatory light chains (RLC) to be mediators of cardiac muscle contraction in both human and animal models, its role was further explored In this study, a detailed characterisation of the physiological changes (i.e., isometric force, calcium sensitivity and sarcomeric protein phosphorylation) was assessed in an MI mouse model, between 2D (2 days) and 28D post-MI, and the changes were related to the phosphorylation status of RLCs. MI mouse models were created via complete ligation of left anterior descending (LAD) coronary artery. Left ventricular (LV) papillary muscles were isolated and permeabilised for isometric force and Ca2+ sensitivity measurement, while the LV myocardium was used to assay sarcomeric proteins’ (RLC, troponin I (TnI) and myosin binding protein-C (MyBP-C)) phosphorylation levels and enzyme (myosin light chain kinase (MLCK), zipper interacting protein kinase (ZIPK) and myosin phosphatase target subunit 2 (MYPT2)) expression levels. Finally, the potential for improving the contractility of diseased cardiac papillary fibres via the enhancement of RLC phosphorylation levels was investigated by employing RLC exchange methods, in vitro. RLC phosphorylation and isometric force potentiation were enhanced in the compensatory phase and decreased in the decompensatory phase of HF failure progression, respectively. There was no significant time-lag between the changes in RLC phosphorylation and isometric force during HF progression, suggesting that changes in RLC phosphorylation immediately affect force generation. Additionally, the in vitro increase in RLC phosphorylation levels in 14D post-MI muscle segments (decompensatory stage) enhanced its force of isometric contraction, substantiating its potential in HF treatment. Longitudinal observation unveils potential mechanisms involving MyBP-C and key enzymes regulating RLC phosphorylation, such as MLCK and MYPT2 (subunit of MLCP), during HF progression. This study primarily demonstrates that RLC phosphorylation is a key sarcomeric protein modification modulating cardiac function. This substantiates the possibility of using RLCs and their associated enzymes to treat HF.

Role of angiotensin-signalling in anthracycline-induced cardiotoxicity

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
S Findlay ◽  
J.H Gill ◽  
R Plummer ◽  
C.J Plummer
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Angiotensin Ii ◽  
Late Onset ◽  
Left Ventricular Systolic Dysfunction ◽  
Left Ventricular ◽  
Cardiomyocyte Hypertrophy ◽  
Funding Source ◽  
Study Results

Abstract   Anthracycline chemotherapy remains a key component of cancer treatment regimens in both paediatric and adult patients. A significant issue with their use is the development of anthracycline-induced cardiotoxicity (AIC), with subclinical AIC and clinical heart failure observed in 13.8% and 3.1% of patients, respectively. The major clinical complication of AIC is the development of late-onset cardiotoxicity, occurring several years after drug administration, presenting as life-threatening heart failure (HF). Determining the relationship between subclinical AIC and late-onset HF, strategies for mitigation of AIC, and impacts upon the cancer survivor population remains a complex challenge. Administration of drugs targeting the angiotensin system, specifically angiotensin converting enzyme inhibitors (ACEi), have been reported to reduce AIC in the clinic. Whilst the therapeutic effect of ACEi in management of left ventricular systolic dysfunction and consequent HF is principally through optimisation of cardiac haemodynamics, the mechanism involved with mitigation of late-onset AIC several years after anthracycline exposure are currently unknown. Using a variety of human cardiomyocyte in vitro models we have previously demonstrated induction of cardiomyocyte hypertrophy by angiotensin II and anthracyclines. Importantly, selective blockade of the angiotensin II receptor 1 (ATR1) on cardiomyocytes mitigated the anthracycline-induced hypertrophic response, implicating synergism between AIC and angiotensin signalling in cardiomyocytes. Adult human ventricular cardiac myocyte AC10 cell-line were treated in vitro with a range of clinically relevant doxorubicin doses for clinically appropriate durations, with AT1 receptor gene expression evaluated using semi-quantitative PCR. Our results confirm a positive correlation between clinically-relevant concentration of doxorubicin and induction of genetic expression of ATR1 in AC10 cells, with up to 200% increases in ATR1 expression observed. Maximal doxorubicin-induced gene expression being observed at 8 and 24-hours, respectively. These preliminary results agreeing with clinical exposure parameters for this drug with protein expression studies being optimised to support these gene expression study results. Our preliminary studies also imply patients developing AIC carry a deleted polymorphism within intron 16 of the ACE gene and increased systemic levels of the ACE product angiotensin II, both with a known association to hypertrophic cardiomyopathy. Taken together, these data support our mechanistic hypothesis that a relationship exists between AIC and modulation of the angiotensin signalling pathway in cardiomyocytes, involving structural cellular changes and asymptomatic cardiac hypertrophy. An elevation in angiotensin II levels, potentially through polymorphisms in ACE, could thereby exacerbate anthracycline-induced hypertrophy and promote the development of late-onset anthracycline-induced HF. Funding Acknowledgement Type of funding source: Private grant(s) and/or Sponsorship. Main funding source(s): Cancer Research UK funded PhD

Abstract 2883: Retroinfusion-facilitated Inotropic AAV9-S100A1 Gene Therapy Restores Global Cardiac Function In A Clinically Relevant Pig Heart Failure Model

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Sven T Pleger ◽  
Changguang Shan ◽  
Jan Kziencek ◽  
Oliver Mueller ◽  
Raffi Bekeredjian ◽  
...  
Keyword(s):  
Heart Failure ◽  
Gene Therapy ◽  
Gene Transfer ◽  
Cardiac Function ◽  
Left Ventricular ◽  
Large Animal ◽  
Circumflex Artery ◽  
Cell Counts ◽  
Clinical Conditions

Background: Cardiac expression of the Ca-dependent inotropic protein S100A1 is decreased in human end-stage heart failure (HF) and cardiomyocyte-targeted viral-based S100A1 gene transfer rescued failing myocardium in small animal models in vivo and in vitro via improved systolic and diastolic sarcoplasmic reticulum Ca-handling. We therefore hypothesized that cardioselective AAV9-S100A1 gene therapy will improve cardiac performance in a large animal experimental HF model under clinical conditions. Methods and Results: Left ventricular (LV) posterolateral myocardial infarction (MI) was induced in pigs by occlusion of the left coronary circumflex artery and resulted in LV failure (HF) 2 weeks post-MI reflected by a 40% and 27% reduction in LV +dp/dt max. and EF, respectively, as assessed by LV catheterization and echocardiography. Post-MI HF pigs were then randomized for retroinfusion of AAV9-luciferase (luc; n=6, 1.5×10 13 total viral particles, tvp) and AAV9-S100A1 (S100A1; n=6, 1.5×10 13 tvp) driven by a cardioselective promoter via the anterior cardiac vein while the left anterior descending artery was temporarily occluded. 14 weeks after cardiac gene transfer, the S100A1-treated HF group showed significantly enhanced S100A1 protein expression (+46.7±17.9%, P<0.05 vs. control groups) in targeted remote LV myocardium and improved indices of cardiac function and remodeling (luc vs. S100A1: +dp/dtmax: 983±81 vs. 1526±83 mmHg/s, EF: 39±2.1 vs. 61±3.7 %, P<0.05 S100A1 vs. luc, LV endsystolic diameter: luc 4.45±0.1 vs. S100A1 3.43 ±0.1 cm, P<0.05 S100A1 vs. luc, HR: 72±4 vs. 69±2, beats/min, P=n.s. S100A1 vs. luc). Importantly, analyses of renal, hepatic and hematopoetic function showed no alteration as assessed by unchanged transaminases, retention values and white blood cell counts compared to sham pigs. Conclusions: Our translational study provides proof of concept that AAV9-S100A1 based HF gene therapy is feasible and restores cardiac function in a large animal HF model under clinical conditions. Next, certified toxicological analysis and different AAV9-S100A1 dosage protocols will be assessed to eventually advance to first phase I/II clinical studies determining therapeutic efficiency of cardiac S100A1 gene therapy in HF patients.

Abstract P020: A Bioengineered Neonatal Cardiomyocyte Scaffold Promotes Cell Survival and Improves Left Ventricular Function in Rats with Heart Failure

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Jordan Lancaster ◽  
Elizabeth Juneman ◽  
Nicholle Johnson ◽  
Joseph Bahl ◽  
Steven Goldman
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Cell Survival ◽  
Cell Tracking ◽  
Left Ventricular ◽  
Neonatal Rat ◽  
Lv Function ◽  
Coronary Artery Ligation ◽  
Neonatal Cardiomyocyte

Background: Cell-based regenerative therapies hold promise as a new treatment for heart failure. Tissue engineered scaffolds used for cell delivery enhance potential improvements in cardiac function by providing the structural and nutrient support for transplanted cell survival, integration, and re-population of injured tissues. Previously, our laboratory reported improvements in left ventricular (LV) function in rats with chronic heart failure (CHF) after placement of a neonatal cardiomyocyte (NCM) seeded 3-dimensional fibroblast construct (3DFC). In brief, 3 weeks after implantation of the NCM-3DFC, LV function improves by increasing (p<0.05) ejection fraction 26% and cardiac index 33%, while decreasing (p<0.05) LV end diastolic pressure 38%. The current report focuses on NCM survival and LV improvements out to 7 weeks post NCM-3DFC implantation. Methods and Results: Cardiomyocytes were isolated from neonatal rat hearts and seeded onto a 3DFC. We evaluated NCM-3DFC in vitro for cellular organization and the presence of functional gap junctions, which demonstrated extensive cell-to-cell connectivity. At 5 days in culture, the seeded patch contracted spontaneously in a rhythmic and directional fashion, beating at 43±3 beats/min with a mean displacement of 1.3±0.3 mm and contraction velocity of 0.8±0.2 mm/sec. The seeded patch could be electrically paced at near physiological rates (270±30 beats/min) while maintaining coordinated, directional contractions. For in vivo evaluation, rats underwent coronary artery ligation and allowed to recover for 3 weeks to establish CHF. NCM-3DFC were implanted 3 weeks after ligation and evaluated 3 and 7 weeks later (6 and 10 weeks after ligation respectively). Live cell tracking of implanted NCM using Q-Dots revealed ∼9% survival of transplanted cells 3 weeks after implantation. In addition, improvements in LV function continued at 7 weeks after implantation of the NCM-3DFC by increasing (p<0.05) ejection fraction 37%. Conclusion: A multicellular, electromechanically organized, cardiomyocyte scaffold, engineered in vitro can improve LV function when implanted directly on the hearts of rats with CHF; the transplanted cells survive and improve LV function chronically.

Serine Mutations in Hsp27 abrogate its ability to inhibit p53 dependent apoptosis and Doxorubicin-induced Heart Failure in mice

2021 ◽  
Author(s):  
Ragu Kanagasabai ◽  
Krishnamurthy Karthikeyan ◽  
Jay L. Zweier ◽  
Govindasamy Ilangovan
Keyword(s):  
Heart Failure ◽  
Heat Shock ◽  
Left Ventricular ◽  
Serine Phosphorylation ◽  
Apoptotic Pathway ◽  
Mtor Phosphorylation ◽  
Inner Diameter ◽  
Shock Proteins ◽  
Parp 1

Small heat shock proteins (sHsps) protect the heart from chemotherapeutics-induced heart failure, by inhibiting p53-dependant apoptosis. However, mechanism of such protection has not been elucidated yet. Here we test a hypothesis that serine phosphorylation of sHsps is essential to inhibit the Doxorubicin-induced p53-dependent apoptotic pathway. Three transgenic mice (TG) lines with cardiomyocyte specific overexpression of human heat shock protein 27 (hHsp27), namely, wild type (MHC-hHsp27), S82A single mutant (MHC-mut-hHsp27(S82A) and tri-mutant (MHC-mut-hHsp27(S15A/S78A/S82A)) were generated. TG mice were treated with Dox (6mg/kg body weight; once in a week; 4 weeks) along with age-matched non-transgenic (Non-TG) controls. The Dox-treated MHC-hHsp27 mice showed improved survival and cardiac function (both MRI and echocardiography), in terms of contractility (%EF) and left ventricular inner diameter (LVID), compared to the Dox-treated Non-TG mice. However, both MHC-mut-hHsp27(S82A) and MHC-mut-hHsp27(S82A/S15A/S76A) mutants overexpressing TG mice did not show such a cardioprotection. Furthermore, transactivation of p53 was found to be attenuated only in Dox-treated MHC-hHsp27 mice-derived cardiomyocytes in vitro, as low p53 was detected in the nuclei, not in mutant hHsp27 overexpressing cardiomyocytes. Similarly, only in MHC-hHsp27 overexpressing cardiomyocytes, low Bax, higher mTOR phosphorylation and low apoptotic PARP-1 cleavage (89kDa fragment) were detected. Pharmacological inhibition of p53 was more effective in mutant-TG mice, compared to MHC-hHsp27 mice. We conclude that phosphorylation of overexpressed Hsp27 at S82 and its association with p53 is essential for the overall cardioprotective effect of Hsp27 against Dox-induced dilated cardiomyopathy. Only phosphorylated Hsp27 protect the heart by inhibiting p53 transactivation.

Abstract 958: Cardiac MyBP-C Modulates Actomyosin Interactions: Evidence From Cardiac MyBP-c−/ − Mice

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Yves Lecarpentier ◽  
Nicolas Vignier ◽  
Patricia Oliviero ◽  
Miguel Cortes-Morichetti ◽  
Lucie Carrier ◽  
...  
Keyword(s):  
Thin Filament ◽  
Isometric Force ◽  
Binding Protein ◽  
Critical Role ◽  
Cardiac Contractility ◽  
Left Ventricular ◽  
Actin Binding ◽  
Power Stroke ◽  
Shortening Velocity

The precise role of cardiac myosin binding protein C (cMyBP-C) on actomyosin interaction (AMI) remains unknown. We hypothesized that the lack of cMyBP-C impaired cardiac AMI. Experiments were performed on 16 weeks old cMyBP-C −/− (KO) and age-matched wild-type (WT) mice (n=20/group). In vitro mechanical and energetics properties were performed on left ventricular (LV) papillary muscles and Huxley’s equations were used to characterize AMI. In vitro motility assays were performed using myosin purified from LV. Myosin-based sliding velocities of actin filaments were analyzed at baseline, after pretreatment of the myosin solution with 10 umol of the catalytic subunit of PKA and/or in the presence of increasing amount of α-actinin, an actin-binding protein that acts as an internal load thereby providing an index of relative isometric force. Western-blot analysis was used to quantify cMyBP-C and phosphorylated cMyBP-C in myosin solutions. Compared to WT, both total tension and maximum shortening velocity were lower in KO (p<0.001). The probability for myosin to be weakly bound to actin was higher in KO than in WT (8.6±0.3 vs. 5.4±0.2%, p<0.05), whereas the number of strongly bound, high-force generated state cross-bridges was lower in KO (6.4±0.9 vs. 11.6±1.0 10 9 /mm 2 , p<0.001). The unitary force per AMI was lower in KO than in WT (p<0.01). At baseline, myosin-based velocities of actin were slower in KO than in WT (1.65±0.01 vs. 1.98±0.01 um/s, p<0.01). The minimum amount of α-actinin needed to completely arrest the thin filament motility was significantly higher in WT than in KO (73.3±1.1 vs 29.1±0.1 ug/l, p<0.001). As expected, cMyBP-C was present in WT myosin solution whereas cMyBP-C was not detected in KO. In WT, PKA induced a 1.6-fold increased in cMyBP-C phosphorylation (p<0.01) associated with a 53±1% increase in the amount of α-actinin required to arrest thin filament motility (p<0.001). PKA did not modify sliding velocity in WT. In KO, PKA had no effect on myosin sliding. We conclude that cMyBP-C regulates AMI by limiting inefficient cross-bridge formation and by enhancing the power stroke step. Phosphorylation status of cMyBP-C appears to play a critical role on cardiac contractility through a direct effect on the myosin molecular motor.

Abstract 285: Cardiac Inflammation and Fibrosis Induced by Heart Failure Are Reversed by Short-Duration Estrogen Therapy

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Andrea Iorga ◽  
Rangarajan Nadadur ◽  
Salil Sharma ◽  
Jingyuan Li ◽  
Mansoureh Eghbali
Keyword(s):  
Heart Failure ◽  
Estrogen Therapy ◽  
Pressure Overload ◽  
Decompensated Heart Failure ◽  
Left Ventricular ◽  
Neonatal Rat ◽  
In Vivo Model ◽  
Anti Inflammatory

Heart failure is generally characterized by increased fibrosis and inflammation, which leads to functional and contractile defects. We have previously shown that short-term estrogen (E2) treatment can rescue pressure overload-induced decompensated heart failure (HF) in mice. Here, we investigate the anti-inflammatory and anti-fibrotic effects of E2 on reversing the adverse remodeling of the left ventricle which occurs during the progression to heart failure. Trans-aortic constriction procedure was used to induce HF. Once the ejection fraction reached ∼30%, one group of mice was sacrificed and the other group was treated with E2 (30 αg/kg/day) for 10 days. In vitro, co-cultured neonatal rat ventricular myocytes and fibroblasts were treated with Angiotensin II (AngII) to simulate cardiac stress, both in the presence or absence of E2. In vivo RT-PCR showed that the transcript levels of the pro-fibrotic markers Collagen I, TGFβ, Fibrosin 1 (FBRS) and Lysil Oxidase (LOX) were significantly upregulated in HF (from 1.00±0.16 to 1.83±0.11 for Collagen 1, 1±0.86 to 4.33±0.59 for TGFβ, 1±0.52 to 3.61±0.22 for FBRS and 1.00±0.33 to 2.88±0.32 for LOX) and were reduced with E2 treatment to levels similar to CTRL. E2 also restored in vitro AngII-induced upregulation of LOX, TGFβ and Collagen 1 (LOX:1±0.23 in CTRL, 6.87±0.26 in AngII and 2.80±1.5 in AngII+E2; TGFβ: 1±0.08 in CTRL, 3.30±0.25 in AngII and 1.59±0.21 in AngII+E2; Collagen 1: 1±0.05 in CTRL.2±0.01 in AngII and 0.65±0.02 (p<0.05, values normalized to CTRL)). Furthermore, the pro-inflammatory interleukins IL-1β and IL-6 were upregulated from 1±0.19 to 1.90±0.09 and 1±0.30 to 5.29±0.77 in the in vivo model of HF, respectively, and reversed to CTRL levels with E2 therapy. In vitro, IL-1β was also significantly increased ∼ 4 fold from 1±0.63 in CTRL to 3.86±0.14 with AngII treatment and restored to 1.29±0.77 with Ang+E2 treatment. Lastly, the anti-inflammatory interleukin IL-10 was downregulated from 1.00±0.17 to 0.49±0.03 in HF and reversed to 0.67±0.09 in vivo with E2 therapy (all values normalized to CTRL). This data strongly suggests that one of the mechanisms for the beneficial action of estrogen on left ventricular heart failure is through reversal of inflammation and fibrosis.

scholarly journals High-Sensitive Troponin I and Re-Hospitalization in Patients With Decompensated Congestive Heart Failure

2019 ◽  
Author(s):  
Shokoufeh Hajsadeghi ◽  
Yaghoub Bagheri ◽  
Mohammad Hossein Ghafouri ◽  
Scott Reza Jafarian Kerman ◽  
Morteza Hassanzadeh
Keyword(s):  
Heart Failure ◽  
Troponin I ◽  
Decompensated Heart Failure ◽  
Left Ventricular ◽  
Hospitalized Patients ◽  
Post Discharge ◽  
Shock Delivery ◽  
Coronary Syndrome ◽  
Patients With Heart Failure

Abstract- Patients with heart failure (HF) are frequently admitted for episodes of decompensation. Cardiac troponins are easily accessible biomarkers role of which for risk stratification of re-hospitalization among HF patients is less certain. We aimed to evaluate high-sensitive cardiac troponin I (hs-cTnI) levels among re-hospitalized patients with decompensated heart failure (D-HF). Consecutive subjects admitted with D-HF to 2 hospitals in Tehran, during the year 2014 were recruited. Excluded ones were patients with a suspected acute coronary syndrome or myocarditis/pericarditis, those with cardiopulmonary resuscitation/DC shock delivery, or major complications during or after hospitalization. Along with echocardiography parameters, level of hs-cTnI was checked at the first hour of hospitalization and 3 months after discharge. The patients were then categorized according to having or not having re-hospitalization during 3 months post discharge. A total of 97 patients were finally recruited. Among re-hospitalized patients, Left ventricular (LV) ejection fraction was significantly lower (38±14 % vs. 50 ± 12%; P=0.001), and LV end-systolic dimension was significantly higher (44±9 mm vs. 38±11 mm; P=0.012) compared to the other group. Moreover, levels of hs-cTnI were significantly higher among the re-hospitalized patients, both at initial visit (0.66±0.43 ng/ml vs 0.51±0.14 ng/ml, respectively; P=0.017) and at 3 months (0.59±0.48 ng/ml vs 0.48±0.23 ng/ml, respectively; P=0.030). This prospective study demonstrated that levels of hs-cTnI (both at the base and at follow up) are higher among patients who readmitted during 3 months of hospitalization for D-HF.

scholarly journals Contractile protein phosphorylation predicts human heart disease phenotypes

2013 ◽  
Vol 304 (12) ◽  
pp. H1644-H1650 ◽  
Author(s):  
Lori A. Walker ◽  
David A. Fullerton ◽  
Peter M. Buttrick
Keyword(s):  
Heart Failure ◽  
Heart Disease ◽  
Protein Phosphorylation ◽  
Protein Phosphatase ◽  
Human Heart ◽  
Troponin I ◽  
Systolic Function ◽  
Left Ventricular ◽  
Control Group ◽  
Lv Function

Human heart failure has been associated with a low level of thin-filament protein phosphorylation and an increase in calcium sensitivity of contraction relative to both “control” human heart tissue and tissue from small animal models. However, diverse strategies of human tissue procurement and the reliance on tissue obtained from subjects with end-stage heart failure suggest this may be an incomplete characterization. Therefore, we evaluated cardiac left ventricular (LV) biopsy samples from patients with aortic stenosis undergoing valve replacement who presented either with LV hypertrophy and preserved systolic function (Hyp) or with LV dilation and reduced ejection fraction (Dil). In Hyp, total troponin I (TnI) phosphorylation was markedly increased and myosin light chain 2 (MLC2) phosphorylation was unchanged relative to a control group of patients with normal LV function. Conversely, in Dil, total TnI phosphorylation was significantly reduced compared with control subjects and MLC2 phosphorylation was increased. Site-specific analysis of TnI phosphorylation revealed phenotype-specific differences such that Hyp samples demonstrated significant increases in phosphorylation at serine 22/23 and Dil samples had significant decreases at serine 43. The ratio of phosphorylation at the two sites was biased toward serine 22/23 in Hyp and toward serine 43/45 in Dil. Western blot analysis showed that protein phosphatase-1 was reduced in Hyp and protein phosphatase-2 was reduced in Dil. These data suggest that posttranslational modifications of sarcomeric proteins, both singly and in combination, are stage specific. Defining these changes in progressive heart disease may provide important diagnostic and treatment information.

Abstract 2523: Azelnidipine Enhances Beneficial Effects of Olmesartan on Left Ventricular Remodeling During the Development of Hypertension-induced Heart Failure

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Xian Wu Cheng ◽  
Kenji Okumura ◽  
Kohzo Nagata ◽  
Aiko Inoue ◽  
Jie Zhang ◽  
...  
Keyword(s):  
Heart Failure ◽  
Nadph Oxidase ◽  
Ventricular Remodeling ◽  
Left Ventricular Remodeling ◽  
Left Ventricular ◽  
Oxidase Inhibitor ◽  
List Type ◽  
Superoxide Anion Production ◽  
Cardioprotective Effects

Objective: This work was undertaken to investigate the comparative effect of angiotensin II type 1 receptor blocker (ARB) and a combination of ARB and calcium channel blocker (CCB) on left ventricular (LV) remodeling during the development of hypertensive heart failure (H-HF). Methods and Results: We treated 8% salt-loaded Dahl salt-sensitive hypertensive rats (n = 10 for each group) with vehicle, hydralazine (5 mg/kg/d), olmesartan (OLM, 5 mg/kg/d), or combined OLM and azelnidipine (AZE, 2mg/kg/d) for 8 weeks. The rats fed 0.3% salt served as age-matched controls. The abundance of Cat mRNAs and proteins were localized in cardiac myocytes (CMCs), and Cat-dependent activities were increased by 4.1-fold in the LV of H-HF rats (n = 8, P< 0.001) and were reduced by OLM treatment. OLM suppressed the elastic lamina degradation concomitant with decreased local Cat S expression in intracoronary smooth muscle cells (SMCs) and restored the balance of elastin to collagen in the LV tissue of H-HF rats (H-HF 4.6 ± 0.9% vs. OLM 15.5 ± 2.1% elastin content/collagen content (%), n = 6, P< 0.0±1; control 22±2.1%). OLM suppressed not only macrophage infiltration but also levels of NADPH oxidase components (p22 phox , gp91 phox , and p47 phox ) concomitant with decreased NADPH activity and O2- production in LV tissues of H-HF rats. Along with its comparable anti-inflammatory effect, add-on AZE further improved all of these parameter changes by OLM. Furthermore, combination therapy significantly enhanced the improvement of LV fibrosis, hypertrophy, stiffness, and dysfunction by OLM. In vitro, H 2 O 2 stimulated Cat S mRNA and protein expression and activity, and these increases were abolished by pretreatment with the antioxidants such as MnTmPyp (50 μmol/L) and N-acetylcysteine (5 mmol/L) as well as a NADPH oxidase inhibitor apocynin (100 μmol/L) in culture CMCs, SMCs, and macrophages (n = 6, P< 0.01). Conclusions: OLM and a combination of OLM and AZE exerted cardioprotective effects in hypertensive HF, via elastolytic Cat activation inhibition by the reduction of NADPH oxidase-dependent superoxide anion production. AZE enhanced the cardioprotective effects of OLM. Thus, the combination of ARB with CBB is a promising potential therapeutic strategy for H-HF.

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