Abstract 305: Pressure Overload-Induced Myocardial Hypertrophy Causes an Electrical Remodeling of CLC-3 Chloride Channels in Mouse Heart

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Dayue D Duan ◽  
Ying Yu ◽  
Guanlei Wang ◽  
Lingyu L Ye ◽  
Yi-gang Li
Keyword(s):  
Heart Failure ◽  
Chloride Channels ◽  
Myocardial Hypertrophy ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Cell Swelling ◽  
Protective Mechanism ◽  
Electrical Remodeling ◽  
Mouse Heart ◽  
Constitutive Activation

Backgrand: Myocardial hypertrophy causes an increase in myocyte volume and constitutive activation of a volume-sensitive outwardly-rectifying anion channel (VSORAC). The underlying molecular mechanisms and function of VSORAC in the electrical remodeling during myocardial hypertrophy and heart failure remain undefined. We tested whether cardiac CLC-3 chloride channels play a role in the hypertrophy-induced electrophysiological remodeling. Methods and Results: The age-matched CLC-3 knockout (Clcn3-/-) mice and their wild-type (Clcn3+/+) littermates were subjected to minimally-invasive transverse aortic banding (MTAB). In 77% (44/57) left ventricular (LV) myocytes isolated from MTAB-Clcn3+/+ mice a large VSORAC current was activated under isotonic conditions. Hypotonic cell-swelling caused no changes in the VSORAC but hypertonic cell-shrinkage significantly inhibited it. This constitutively-activated VSORAC had an anion selectivity of I->Cl->Asp-, and was inhibited by tamoxifen, PKC activation and intracellular application of anti-CLC-3 antibody. In the age-matched MTAB-Clcn3-/- mice, a significantly smaller outwardly-rectifying current was present in only 38% (36/94, P<0.05 vs MTAB-Clcn3+/+) LV myocytes. This current was neither increased by hypotonic stress nor inhibited by tamoxifen, PKC or anti-CLC-3 antibody, indicating not a VSORAC or CLC-3 current. Expression of CLC-3 protein was significantly increased in the LV tissues of MTAB-Clcn3+/+ mice but not in Sham-Clcn3+/+ and MTAB-Clcn3-/- mice. Both surface and intracardiac electrophysiological recordings revealed more atrial or ventricular arrhythmias in MTAB-Clcn3-/- mice than in MTAB- and Sham-Clcn3+/+ mice. Conclusions: Pressure-overload-induced myocardial hypertrophy causes an upregulation of CLC-3 expression and constitutive activation of CLC-3 may serve as a novel protective mechanism against the electrical remodeling during myocardial hypertrophy and heart failure.

scholarly journals MitoQ regulates redox-related noncoding RNAs to preserve mitochondrial network integrity in pressure-overload heart failure

2020 ◽  
Vol 318 (3) ◽  
pp. H682-H695 ◽  
Author(s):  
Seulhee Kim ◽  
Jiajia Song ◽  
Patrick Ernst ◽  
Mary N. Latimer ◽  
Chae-Myeong Ha ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Sarcoplasmic Reticulum ◽  
Posttranscriptional Regulation ◽  
Noncoding Rnas ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Mouse Heart ◽  
Mitochondrial Network ◽  
Mitofusin 2

Evidence suggests that mitochondrial network integrity is impaired in cardiomyocytes from failing hearts. While oxidative stress has been implicated in heart failure (HF)-associated mitochondrial remodeling, the effect of mitochondrial-targeted antioxidants, such as mitoquinone (MitoQ), on the mitochondrial network in a model of HF (e.g., pressure overload) has not been demonstrated. Furthermore, the mechanism of this regulation is not completely understood with an emerging role for posttranscriptional regulation via long noncoding RNAs (lncRNAs). We hypothesized that MitoQ preserves mitochondrial fusion proteins (i.e., mitofusin), likely through redox-sensitive lncRNAs, leading to improved mitochondrial network integrity in failing hearts. To test this hypothesis, 8-wk-old C57BL/6J mice were subjected to ascending aortic constriction (AAC), which caused substantial left ventricular (LV) chamber remodeling and remarkable contractile dysfunction in 1 wk. Transmission electron microscopy and immunostaining revealed defective intermitochondrial and mitochondrial-sarcoplasmic reticulum ultrastructure in AAC mice compared with sham-operated animals, which was accompanied by elevated oxidative stress and suppressed mitofusin (i.e., Mfn1 and Mfn2) expression. MitoQ (1.36 mg·day−1·mouse−1, 7 consecutive days) significantly ameliorated LV dysfunction, attenuated Mfn2 downregulation, improved interorganellar contact, and increased metabolism-related gene expression. Moreover, our data revealed that MitoQ alleviated the dysregulation of an Mfn2-associated lncRNA (i.e., Plscr4). In summary, the present study supports a unique mechanism by which MitoQ improves myocardial intermitochondrial and mitochondrial-sarcoplasmic reticulum (SR) ultrastructural remodeling in HF by maintaining Mfn2 expression via regulation by an lncRNA. These findings underscore the important role of lncRNAs in the pathogenesis of HF and the potential of targeting them for effective HF treatment. NEW & NOTEWORTHY We have shown that MitoQ improves cardiac mitochondrial network integrity and mitochondrial-SR alignment in a pressure-overload mouse heart-failure model. This may be occurring partly through preventing the dysregulation of a redox-sensitive lncRNA-microRNA pair (i.e., Plscr4-miR-214) that results in an increase in mitofusin-2 expression.

scholarly journals The GABAA Receptor Influences Pressure Overload-Induced Heart Failure by Modulating Macrophages in Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Jin Bu ◽  
Shiyuan Huang ◽  
Jue Wang ◽  
Tong Xia ◽  
Hui Liu ◽  
...  
Keyword(s):  
Heart Failure ◽  
Inflammatory Responses ◽  
Myocardial Hypertrophy ◽  
Macrophage Polarization ◽  
Late Phase ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Internal Diameter ◽  
Gamma Aminobutyric Acid ◽  
Reduced Ejection Fraction

BackgroundMyocardial macrophages have key roles in cardiac remodeling and dysfunction. The gamma-aminobutyric acid subtype A (GABAA) receptor was recently found to be distributed in macrophages, allowing regulation of inflammatory responses to various diseases. This study aimed to clarify the role of GABAA receptor-mediated macrophage responses in pressure overload-induced heart failure.Methods and ResultsC57BL/6J mice underwent transverse aortic constriction for pressure-overload hypertrophy (POH) and were intraperitoneally treated with a specific GABAA receptor agonist (topiramate) or antagonist (bicuculline). Echocardiography, histology, and flow cytometry were performed to evaluate the causes and effects of myocardial hypertrophy and fibrosis. Activation of the GABAA receptor by topiramate reduced ejection fraction and fractional shortening, enlarged the end-diastolic and end-systolic left ventricular internal diameter, aggravated myocardial hypertrophy and fibrosis, and accelerated heart failure in response to pressure overload. Mechanistically, topiramate increased the number of Ly6Clow macrophages in the heart during POH and circulating Ly6Chigh classic monocyte infiltration in late-phase POH. Further, topiramate drove Ly6Clow macrophages toward MHCIIhigh macrophage polarization. As a result, Ly6Clow macrophages activated the amphiregulin-induced AKT/mTOR signaling pathway, and Ly6ClowMHCIIhigh macrophage polarization increased expression levels of osteopontin and TGF-β, which led to myocardial hypertrophy and fibrosis. Conversely, GABAA receptor blockage with bicuculline reversed these effects.ConclusionsControl of the GABAA receptor activity in monocytes/macrophages plays an important role in myocardial hypertrophy and fibrosis after POH. Blockade of the GABAA receptor has the potential to improve pressure overload-induced heart failure.

scholarly journals Ablation of cardiac TIGAR preserves myocardial energetics and cardiac function in the pressure overload heart failure model

2019 ◽  
Vol 316 (6) ◽  
pp. H1366-H1377
Author(s):  
Yoshifumi Okawa ◽  
Atsushi Hoshino ◽  
Makoto Ariyoshi ◽  
Satoshi Kaimoto ◽  
Shuhei Tateishi ◽  
...  
Keyword(s):  
Heart Failure ◽  
Pressure Overload ◽  
Cardiac Metabolism ◽  
High Energy ◽  
Left Ventricular ◽  
Lv Function ◽  
Mouse Heart ◽  
High Energy Phosphates ◽  
Wild Type ◽  
Myocardial Energetics

Despite the advances in medical therapy, the morbidity and mortality of heart failure (HF) remain unacceptably high. HF results from reduced metabolism–contraction coupling efficiency, so the modulation of cardiac metabolism may be an effective strategy for therapeutic interventions. Tumor suppressor p53 (TP53) and its downstream target TP53-induced glycolysis and apoptosis regulator (TIGAR) are known to modulate cardiac metabolism and cell fate. To investigate TIGAR’s function in HF, we compared myocardial, metabolic, and functional outcomes between TIGAR knockout (TIGAR−/−) mice and wild-type (TIGAR+/+) mice subjected to chronic thoracic transverse aortic constriction (TAC), a pressure-overload HF model. In wild-type mice hearts, p53 and TIGAR increased markedly during HF development. Eight weeks after TAC surgery, the left ventricular (LV) dysfunction, fibrosis, oxidative damage, and myocyte apoptosis were significantly advanced in wild-type than in TIGAR−/− mouse heart. Further, myocardial high-energy phosphates in wild-type hearts were significantly decreased compared with those of TIGAR−/− mouse heart. Glucose oxidation and glycolysis rates were also reduced in isolated perfused wild-type hearts following TAC than those in TIGAR−/− hearts, which suggest that the upregulation of TIGAR in HF causes impaired myocardial energetics and function. The effects of TIGAR knockout on LV function were also replicated in tamoxifen (TAM)-inducible cardiac-specific TIGAR knockout mice ( TIGARflox/flox/Tg(Myh6-cre/Esr1) mice). The ablation of TIGAR during pressure-overload HF preserves myocardial function and energetics. Thus, cardiac TIGAR-targeted therapy to increase glucose metabolism will be a novel strategy for HF. NEW & NOTEWORTHY The present study is the first to demonstrate that TP53-induced glycolysis and apoptosis regulator (TIGAR) is upregulated in the myocardium during experimental heart failure (HF) in mice and that TIGAR knockout can preserve the heart function and myocardial energetics during HF. Reducing TIGAR to enhance myocardial glycolytic energy production is a promising therapeutic strategy for HF.

scholarly journals Trimetazidine Attenuates Heart Failure by Improving Myocardial Metabolism via AMPK

2021 ◽  
Vol 12 ◽  
Author(s):  
Hongyang Shu ◽  
Weijian Hang ◽  
Yizhong Peng ◽  
Jiali Nie ◽  
Lujin Wu ◽  
...  
Keyword(s):  
Heart Failure ◽  
Glucose Uptake ◽  
Glucose Transporter ◽  
Myocardial Metabolism ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Neonatal Rat ◽  
Mitochondrial Morphology ◽  
Mouse Heart ◽  
Compound C

Energic deficiency of cardiomyocytes is a dominant cause of heart failure. An antianginal agent, trimetazidine improves the myocardial energetic supply. We presumed that trimetazidine protects the cardiomyocytes from the pressure overload-induced heart failure through improving the myocardial metabolism. C57BL/6 mice were subjected to transverse aortic constriction (TAC). After 4 weeks of TAC, heart failure was observed in mice manifested by an increased left ventricular (LV) chamber dimension, an impaired LV ejection fraction evaluated by echocardiography analysis, which were significantly restrained by the treatment of trimetazidine. Trimetazidine restored the mitochondrial morphology and function tested by cardiac transmission electron microscope and mitochondrial dynamic proteins analysis. Positron emission tomography showed that trimetazidine significantly elevated the glucose uptake in TAC mouse heart. Trimetazidine restrained the impairments of the insulin signaling in TAC mice and promoted the translocation of glucose transporter type IV (GLUT4) from the storage vesicle to membrane. However, these cardioprotective effects of trimetazidine in TAC mice were notably abolished by compound C (C.C), a specific AMPK inhibitor. The enlargement of neonatal rat cardiomyocyte induced by mechanical stretch, together with the increased expression of hypertrophy-associated proteins, mitochondria deformation and dysfunction were significantly ameliorated by trimetazidine. Trimetazidine enhanced the isolated cardiomyocyte glucose uptake in vitro. These benefits brought by trimetazidine were also removed with the presence of C.C. In conclusion, trimetazidine attenuated pressure overload-induced heart failure through improving myocardial mitochondrial function and glucose uptake via AMPK.

Myeloid-Derived Growth Factor Protects Against Pressure Overload-Induced Heart Failure by Preserving Sarco/Endoplasmic Reticulum Ca 2+ -ATPase Expression in Cardiomyocytes

Circulation ◽  
2021 ◽  
Author(s):  
Mortimer Korf-Klingebiel ◽  
Marc R. Reboll ◽  
Felix Polten ◽  
Natalie Weber ◽  
Felix Jäckle ◽  
...  
Keyword(s):  
Heart Failure ◽  
Bone Marrow ◽  
Endoplasmic Reticulum ◽  
Growth Factor ◽  
Plasma Concentrations ◽  
Pressure Overload ◽  
Inflammatory Cells ◽  
Left Ventricular ◽  
Neonatal Rat ◽  
Wild Type

Background: Inflammation contributes to the pathogenesis of heart failure, but there is limited understanding of inflammation's potential benefits. Inflammatory cells secrete myeloid-derived growth factor (MYDGF) to promote tissue repair after acute myocardial infarction. We hypothesized that MYDGF has a role in cardiac adaptation to persistent pressure overload. Methods: We defined the cellular sources and function of MYDGF in wild-type, Mydgf -deficient ( Mydgf -/- ), and Mydgf bone marrow-chimeric or bone marrow-conditional transgenic mice with pressure overload-induced heart failure after transverse aortic constriction surgery. We measured MYDGF plasma concentrations by targeted liquid chromatography-mass spectrometry. We identified MYDGF signaling targets by phosphoproteomics and substrate-based kinase activity inference. We recorded Ca 2+ transients and sarcomere contractions in isolated cardiomyocytes. Additionally, we explored the therapeutic potential of recombinant MYDGF. Results: MYDGF protein abundance increased in the left ventricular (LV) myocardium and in blood plasma of pressure-overloaded mice. Patients with severe aortic stenosis also had elevated MYDGF plasma concentrations, which declined after transcatheter aortic valve implantation. Monocytes and macrophages emerged as the main MYDGF sources in the pressure-overloaded murine heart. While Mydgf -/- mice had no apparent phenotype at baseline, they developed more severe LV hypertrophy and contractile dysfunction during pressure overload than wild-type mice. Conversely, conditional transgenic overexpression of MYDGF in bone marrow-derived inflammatory cells attenuated pressure overload-induced hypertrophy and dysfunction. Mechanistically, MYDGF inhibited G protein coupled receptor agonist-induced hypertrophy and augmented sarco/endoplasmic reticulum Ca 2+ ATPase 2a (SERCA2a) expression in cultured neonatal rat cardiomyocytes by enhancing PIM1 serine/threonine kinase expression and activity. Along this line, cardiomyocytes from pressure-overloaded Mydgf -/- mice displayed reduced PIM1 and SERCA2a expression, greater hypertrophy, and impaired Ca 2+ cycling and sarcomere function compared to cardiomyocytes from pressure-overloaded wild-type mice. Transplanting Mydgf -/- mice with wild-type bone marrow cells augmented cardiac PIM1 and SERCA2a levels and ameliorated pressure overload-induced hypertrophy and dysfunction. Pressure-overloaded Mydgf -/- mice were similarly rescued by adenoviral Serca2a gene transfer. Treating pressure-overloaded wild-type mice subcutaneously with recombinant MYDGF enhanced SERCA2a expression, attenuated LV hypertrophy and dysfunction, and improved survival. Conclusions: These findings establish a MYDGF-based adaptive crosstalk between inflammatory cells and cardiomyocytes that protects against pressure overload-induced heart failure.

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.

Abstract 47: GATA Factors Caught at a Crossroad of Gene Duplication with Functional Divergence

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Jop H van Berlo ◽  
Jeffery D Molkentin
Keyword(s):  
Heart Failure ◽  
Functional Divergence ◽  
Severe Heart Failure ◽  
Pressure Overload ◽  
Mouse Heart ◽  
Adult Heart ◽  
Functional Roles ◽  
Hypertrophic Response ◽  
Gata Factors ◽  
Cardiac Gene

Background Six individual members comprise the GATA family of Zn finger-containing transcription factors that play major roles in the hematopoietic system and many mesoderm and endoderm derived tissues. The adult heart expresses both GATA4 and GATA6. Here, we examined the overlapping and diverging functional roles of GATA4 and GATA6 in the adult heart, both at baseline and under stress. Results Pressure overload by transverse aortic constriction (TAC) caused a blunted hypertrophic response when GATA4 was deleted from the adult heart, with severe heart failure ensuing after 4 weeks. Similarly, deletion of GATA6 from the mouse heart showed a blunted hypertrophic response and heart failure. Next, we deleted 1 allele of GATA4 and 1 allele of GATA6 from the adult heart, also resulting in blunted hypertrophy and cardiac dysfunction. Deletion of all four alleles of GATA4 and 6 resulted in spontaneous heart failure and death by 3 months of age. These results suggested functional overlap or synergistic activation. To address this concept more directly we deleted GATA6 from the adult heart and overexpressed either GATA4 or GATA6 in a cardiac-specific manner. As expected, we were able to completely revert the phenotype to wild type when GATA6 was overexpressed in mice that had GATA6 genetically deleted. Surprisingly, overexpression of GATA4 was unable to rescue the absence of GATA6 and actually worsened cardiac function in response to pressure overload. Possible explanations for this functional divergence were suggested by an observed rarefaction in capillaries of the heart in absence of GATA4, but enhanced angiogenesis in absence of GATA6. Moreover, when we induced cardiac hypertrophy through MAPK activation, we observed a critical necessity for GATA4, while GATA6 was dispensable. Conclusion Although GATA4 and 6 may be functionally complementary for cardiac gene expression and hypertrophy, they evolved some specific roles in the heart, such as angiogenesis and stress activation. We are currently unraveling how GATA4 and 6 may differentially regulate genes.

Abstract 238: Loss of AKAP150 Promotes Pathological Remodeling and Heart Failure Propensity by Disrupting Calcium Homeostasis and Contractile Reserve

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Lei Li ◽  
Jing Li ◽  
Benjamin Drum ◽  
Yi Chen ◽  
Haifeng Yin ◽  
...  
Keyword(s):  
Heart Failure ◽  
Critical Role ◽  
Pressure Overload ◽  
Contractile Reserve ◽  
Mouse Heart ◽  
Adrenergic Stimulation ◽  
Anchoring Protein ◽  
Key Aspects ◽  
Myocyte Contractility ◽  
Pathological Remodeling

Impaired Ca 2+ cycling and myocyte contractility are a hallmark of heart failure triggered by pathological stress such as hemodynamic overload. The A-Kinase anchoring protein AKAP150 has been shown to coordinate key aspects of adrenergic regulation of Ca 2+ cycling and excitation-contraction in cardiomyocytes. However, the role of the AKAP150 signaling complexes in the pathogenesis of heart failure is largely unknown. Here we investigate how AKAP150 signaling complexes impact Ca 2+ cycling, myocyte contractility, and heart failure susceptibility following pathological stress. We detected a significant reduction of AKAP150 expression in the failing mouse heart induced by pressure overload. Importantly, cardiac-specific AKAP150 knockout mice were predisposed to develop dilated cardiomyopathy with severe cardiac dysfunction and fibrosis after pressure overload. Loss of AKAP150 also promoted pathological remodeling and heart failure progression following myocardial infarction. However, ablation of AKAP150 did not appear to affect chronic activation of calcineurin-NFAT signaling in cardiomyocytes or pressure overload- or agonist- induced cardiac hypertrophy. Immunoprecipitation studies showed that AKAP150 was associated with SERCA2, phospholamban, and ryanodine receptor-2, providing a targeted control of sarcoplasmic reticulum Ca 2+ regulatory proteins. Mechanistically, loss of AKAP150 led to impaired Ca 2+ cycling and reduced myocyte contractility reserve following adrenergic stimulation or pressure overload. These findings define a critical role for AKAP150 in maintaining Ca 2+ homeostasis and myocardial ionotropy following pathological stress, suggesting the AKAP150 signaling pathway may serve as a novel therapeutic target for heart failure.

Abstract 14952: Hemodynamic Comparison of Left Ventricular Function in Pressure Overload- versus Volume Overload-Induced Heart Failure Models by Invasive Pressure-Volume Analysis

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Mihály Ruppert ◽  
Christian Karime ◽  
Alex A Sayour ◽  
Attila Oláh ◽  
Dávid Nagy ◽  
...  
Keyword(s):  
Heart Failure ◽  
Systolic Function ◽  
Pressure Overload ◽  
Volume Overload ◽  
Detailed Comparison ◽  
Left Ventricular ◽  
Lv Function ◽  
Arterial Elastance ◽  
Lv Remodeling ◽  
Av Shunt

Introduction: Both sustained left ventricular (LV) pressure overload (PO) and volume overload (VO) induces LV remodeling and eventually development of heart failure (HF). Using rat models, the present study aimed to provide a detailed comparison of distinct aspects of LV function in PO- and VO-induced HF. Methods: PO and VO was induced by transverse aortic constriction (TAC, n=12) and aortocaval shunt (AV-shunt, n=12) creation respectively. Controls underwent corresponding sham operations (n=11). LV remodeling was characterized by echocardiography, histology, qRT PCR, and western blot. LV function was assessed by invasive pressure-volume (P-V) analysis. Results: Both sustained PO and VO resulted in the development of HF, as evidenced by increased LV BNP mRNA expression, pulmonary edema, and characteristic symptoms. While the extent of LV hypertrophy was comparable between the HF models, PO induced concentric while VO evoked eccentric LV remodeling. P-V analysis revealed impaired systolic function in both HF models. Accordingly, decreased ejection fraction and impaired ventriculo-arterial coupling (calculated as the ratio of arterial elastance/LV contractility [VAC]: 0.38±0.05 vs. 1.30±0.13, ShamTAC vs. TAC and 0.52±0.08 vs. 1.17±0.13, ShamAV-Shunt vs. AV-shunt; p<0.05) was detected in both HF models. However, in case of VO the severely reduced LV contractility (slope of end-systolic P-V relationship: 1.79±0.19 vs. 0.52±0.06, ShamAV-Shunt vs. AV-shunt, p<0.05 and 2.14±0.28 vs. 2.03±0.21, ShamTAC vs. TAC p>0.05) underpinned the contractility-afterload mismatch, while in case of PO the increased afterload (arterial elastance: 0.77±0.07 vs. 2.64±0.28, ShamTAC vs. TAC and 0.80±0.07 vs. 0.54±0.05, ShamAV-Shunt vs. AV-shunt; p<0.05) was the main determinant. Furthermore, prolongation of active relaxation occurred to a greater extent in case of PO. In addition, increased myocardial stiffness was only observed in PO-induced HF. Conclusion: Systolic function was reduced in both HF models. However, different factors underpinned the impaired VAC in case of VO (reduced LV contractility) and PO (increased arterial elastance). Furthermore, although diastolic function deteriorated in both models, it occurred to a greater extent in case of PO.

Cacao Bean Polyphenols Inhibit Cardiac Hypertrophy and Systolic Dysfunction in Pressure Overload-induced Heart Failure Model Mice

Planta Medica ◽  
2020 ◽  
Vol 86 (17) ◽  
pp. 1304-1312
Author(s):  
Nurmila Sari ◽  
Yasufumi Katanasaka ◽  
Hiroki Honda ◽  
Yusuke Miyazaki ◽  
Yoichi Sunagawa ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Gene Transcription ◽  
Binding Protein ◽  
Systolic Dysfunction ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Cardiomyocyte Hypertrophy ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal

AbstractPathological stresses such as pressure overload and myocardial infarction induce cardiac hypertrophy, which increases the risk of heart failure. Cacao bean polyphenols have recently gained considerable attention for their beneficial effects on cardiovascular diseases. This study investigated the effect of cacao bean polyphenols on the development of cardiac hypertrophy and heart failure. Cardiomyocytes from neonatal rats were pre-treated with cacao bean polyphenols and then stimulated with 30 µM phenylephrine. C57BL/6j male mice were subjected to sham or transverse aortic constriction surgery and then orally administered with vehicle or cacao bean polyphenols. Cardiac hypertrophy and function were examined by echocardiography. In cardiomyocytes, cacao bean polyphenols significantly suppressed phenylephrine-induced cardiomyocyte hypertrophy and hypertrophic gene transcription. Extracellular signal-regulated kinase 1/2 and GATA binding protein 4 phosphorylation induced by phenylephrine was inhibited by cacao bean polyphenols treatment in the cardiomyocytes. Cacao bean polyphenols treatment at 1200 mg/kg significantly ameliorated left ventricular posterior wall thickness, fractional shortening, hypertrophic gene transcription, cardiac hypertrophy, cardiac fibrosis, and extracellular signal-regulated kinase 1/2 phosphorylation induced by pressure overload. In conclusion, these findings suggest that cacao bean polyphenols prevent pressure overload-induced cardiac hypertrophy and systolic dysfunction by inhibiting the extracellular signal-regulated kinase 1/2-GATA binding protein 4 pathway in cardiomyocytes. Thus, cacao bean polyphenols may be useful for heart failure therapy in humans.

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