Phosphodiesterase 5 inhibition improves contractile function and restores transverse tubule loss and catecholamine responsiveness in heart failure.
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ABSTRACT:
SUBMITTER: Lawless M
PROVIDER: S-EPMC6494852 | biostudies-other | 2019 May
REPOSITORIES: biostudies-other
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Phosphodiesterase 5 inhibition improves contractile function and restores transverse tubule loss and catecholamine responsiveness in heart failure.
Lawless Michael M Caldwell Jessica L JL Radcliffe Emma J EJ Smith Charlotte E R CER Madders George W P GWP Hutchings David C DC Woods Lori S LS Church Stephanie J SJ Unwin Richard D RD Kirkwood Graeme J GJ Becker Lorenz K LK Pearman Charles M CM Taylor Rebecca F RF Eisner David A DA Dibb Katharine M KM Trafford Andrew W AW
Scientific reports 20190501 1
Heart failure (HF) is characterized by poor survival, a loss of catecholamine reserve and cellular structural remodeling in the form of disorganization and loss of the transverse tubule network. Indeed, survival rates for HF are worse than many common cancers and have not improved over time. Tadalafil is a clinically relevant drug that blocks phosphodiesterase 5 with high specificity and is used to treat erectile dysfunction. Using a sheep model of advanced HF, we show that tadalafil treatment i ...[more]
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Project description:PurposeAdrenomedullin (ADM) has been referred to as a double-edged sword during septic shock: On one hand, ADM supplementation improved organ perfusion and function, attenuated systemic inflammation, and ultimately reduced tissue apoptosis and mortality. On the other hand, ADM overproduction can cause circulatory collapse and organ failure due to impaired vasoconstrictor response and reduced myocardial contractility. Since most of these data originate from un-resuscitated shock models, we tested the hypothesis whether the newly developed anti-ADM antibody HAM1101 may improve catecholamine responsiveness and thus attenuate organ dysfunction during resuscitated murine, cecal ligation and puncture (CLP)-induced septic shock.MethodsImmediately after CLP, mice randomly received vehicle (phosphate-buffered saline, n = 11) or HAM1101 (n = 9; 2 μg·g(-1)). Fifteen hours after CLP, animals were anesthetized, mechanically ventilated, instrumented, and resuscitated with hydroxyethylstarch and continuous i.v. norepinephrine to achieve normotensive hemodynamics (mean arterial pressure > 50 to 60 mmHg).ResultsHAM1101 pretreatment reduced the norepinephrine infusion rates required to achieve hemodynamic targets, increased urine flow, improved creatinine clearance, and lowered neutrophil gelatinase-associated lipocalin blood levels, which coincided with reduced expression of the inducible nitric oxide synthase and formation of peroxynitrite (nitrotyrosine immunostaining) in the kidney and aorta, ultimately resulting in attenuated systemic inflammation and tissue apoptosis.ConclusionsDuring resuscitated murine septic shock, early ADM binding with HAM1101 improved catecholamine responsiveness, blunted the shock-related impairment of energy metabolism, reduced nitrosative stress, and attenuated systemic inflammatory response, which was ultimately associated with reduced kidney dysfunction and organ injury.
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Project description:Subclinical hypothyroidism and low T3 syndrome are commonly associated with an increased risk of cardiovascular disease (CVD) and mortality. We examined effects of T3 on T-tubule (TT) structures, Ca2+ mobilization and contractility, and clustering of dyadic proteins. Thyroid hormone (TH) deficiency was induced in adult female rats by propyl-thiouracil (PTU; 0.025%) treatment for 8 weeks. Rats were then randomized to continued PTU or triiodo-L-thyronine (T3; 10 μg/kg/d) treatment for 2 weeks (PTU + T3). After in vivo echocardiographic and hemodynamic recordings, cardiomyocytes (CM) were isolated to record Ca2+ transients and contractility. TT organization was assessed by confocal microscopy, and STORM images were captured to measure ryanodine receptor (RyR2) cluster number and size, and L-type Ca2+ channel (LTCC, Cav1.2) co-localization. Expressed genes including two integral TT proteins, junctophilin-2 (Jph-2) and bridging integrator-1 (BIN1), were analyzed in left ventricular (LV) tissues and cultured CM using qPCR and RNA sequencing. The T3 dosage used normalized serum T3, and reversed adverse effects of TH deficiency on in vivo measures of cardiac function. Recordings of isolated CM indicated that T3 increased rates of Ca2+ release and re-uptake, resulting in increased velocities of sarcomere shortening and re-lengthening. TT periodicity was significantly decreased, with reduced transverse tubules but increased longitudinal tubules in TH-deficient CMs and LV tissue, and these structures were normalized by T3 treatment. Analysis of STORM data of PTU myocytes showed decreased RyR2 cluster numbers and RyR localizations within each cluster without significant changes in Cav1.2 localizations within RyR clusters. T3 treatment normalized RyR2 cluster size and number. qPCR and RNAseq analyses of LV and cultured CM showed that Jph2 expression was T3-responsive, and its increase with treatment may explain improved TT organization and RyR-LTCC coupling.
| S-EPMC8570994 | biostudies-literature
Project description:Impaired myocardial contractile function is a hallmark of heart failure (HF) which may present under resting conditions and/or during physiological stress. Previous studies reported that high fat feeding in HF is associated with improved myocardial contractile function at baseline. Our goal was to determine whether myocardial function is compromised in response to physiological stress and to evaluate the global gene expression profile of rats fed high dietary fat following infarction. Male Wistar rats underwent ligation or sham surgery and were fed normal (10% kcal fat) (SHAM+NC, HF+NC) or high fat (60% kcal saturated fat) (SHAM+SAT, HF+SAT) for 8 weeks. Myocardial contractile function was assessed using a Millar pressure-volume (PV) conductance catheter at baseline, during inferior vena caval occlusions and dobutamine (DOB) stress. Steady state indices of systolic function, left ventricular (LV)+dP/dtmax, stroke work and maximal power were increased in HF+SAT vs HF+NC; HF+NC were reduced vs SHAM+NC. Preload-recruitable measures of contractility [end systolic PV relationship, maximal elastance, preload recruitable SW and peak+dP/dtmax to end diastolic volume] were decreased in HF+NC but not HF+SAT. β-adrenergic responsiveness (delta-LV+dP/dtmax and delta-cardiac output DOB 0-10 µg•kg-1•min-1) was reduced in HF, but high fat feeding did not further impact contractile reserve in HF. Contractile reserve was reduced by high fat in SHAM+SAT. Microarray gene expression analysis reveals the majority of significantly altered pathways identified to contain multiple gene targets correspond to cell signaling pathways and energy metabolism. These findings suggest that high saturated fat improves myocardial function at rest and during physiological stress in infarcted hearts, but may negatively impact contractile reserve under non-pathological conditions. Furthermore, high fat feeding-induced alterations in gene expression related to energy metabolism and specific signaling pathways reveal promising targets through which high saturated fat potentially mediates cardioprotection in heart failure/LV dysfunction. Comparison of gene expression in heart failure or sham surgery hearts exposed to saturated or normal diets. Male Wistar rats (300-350g) were maintained on a reverse light-dark cycle and all procedures were done 3-6 hours into the dark phase cycle to synchronize with the normal active state of the rodents. Rats were randomly assigned to receive either a sham-operation (SH) or coronary ligation to induce cardiac dysfunction (HF). Heart failure was induced by ligating the left main coronary artery. Following surgery, rats were immediately fed either a normal rodent chow (NC) or a high saturated fat chow (SAT) with 60% caloric content derived from fat (25% palmitic, 33% stearic, 33% oleic acid, Research Diets).
2010-09-01 | E-GEOD-21021 | biostudies-arrayexpress
Project description:BACKGROUND: Skeletal muscle fibres contain transverse tubular (t-tubule) networks that allow electrical signals to rapidly propagate into the fibre. These electrical signals are generated by the transport of ions across the t-tubule membranes and this can result in significant changes in ion concentrations within the t-tubules during muscle excitation. During periods of repeated high-frequency activation of skeletal muscle the t-tubule K+ concentration is believed to increase significantly and diffusive K+ transport from the t-tubules into the interstitial space provides a mechanism for alleviating muscle membrane depolarization. However, the tortuous nature of the highly branched space-filling t-tubule network impedes the diffusion of material through the network. The effective diffusion coefficient for ions in the t-tubules has been measured to be approximately five times lower than in free solution, which is significantly different from existing theoretical values of the effective diffusion coefficient that range from 2-3 times lower than in free solution. To resolve this discrepancy, in this paper we study the process of diffusion within electron microscope scanned sections of the skeletal muscle t-tubule network using mathematical modelling and computer simulation techniques. Our model includes t-tubule geometry, tautness, hydrodynamic and non-planar network factors. RESULTS: Using our model we found that the t-tubule network geometry reduced the K+ diffusion coefficient to 19-27% of its value in free solution, which is consistent with the experimentally observed value of 21% and is significantly smaller than existing theoretical values that range from 32-50%. We also found that diffusion in the t-tubules is anomalous for skeletal muscle fibres with a diameter of less than approximately 10-20 microm as a result of obstructed diffusion. We also observed that the [K+] within the interior of the t-tubule network during high-frequency activation is greater for fibres with a larger diameter. Smaller skeletal muscle fibres are therefore more resistant to membrane depolarization. Because the t-tubule network is anisotropic and inhomogeneous, we also found that the [K+] distribution generated within the network was irregular for fibres of small diameter. CONCLUSION: Our model explains the measured effective diffusion coefficient for ions in skeletal muscle t-tubules.
| S-EPMC1899483 | biostudies-literature
Project description:Sympathetic nervous system (SNS) hyperactivity is characteristic of chronic heart failure (HF) and significantly worsens prognosis. The success of ?-adrenoceptor antagonist (?-blockers) therapy in HF is primarily attributed to protection of the heart from the noxious effects of augmented catecholamine levels. ?-Blockers have been shown to reduce SNS hyperactivity in HF, but the underlying molecular mechanisms are not understood. The GPCR kinase-2 (GRK2)-?(2) adrenoceptor-catecholamine production axis is up-regulated in the adrenal medulla during HF causing ?(2) -adrenoceptor dysfunction and elevated catecholamine levels. Here, we sought to investigate if ?-blocker treatment in HF could lower SNS activation by directly altering adrenal GRK2 levels.Four weeks after myocardial infarction-induced HF, adult rats were randomized to 10-week treatment with vehicle (HF/C) or bisoprolol (HF/B). Cardiac function and dimensions were measured. In heart and adrenal gland, GRK2 levels were assessed by RT-PCR and Western blotting and adrenoceptors studied with radioligand binding. Catecholamines and ?(2) adrenoceptors in adrenal medulla chromaffin cell cultures were also measured.Bisoprolol treatment ameliorated HF-related adverse cardiac remodelling and reduced plasma catecholamine levels, compared with HF/C rats. Bisoprolol also attenuated adrenal GRK2 overexpression as observed in HF/C rats and increased ?(2) adrenoceptor density. In cultures of adrenal medulla chromaffin cells from all study groups, bisoprolol reversed HF-related ?(2) adrenoceptor dysfunction. This effect was reversed by GRK2 overexpression.Blockade of ?-adrenoceptors normalized the adrenal ?(2) adrenoceptor-catecholamine production axis by reducing GRK2 levels. This effect may contribute significantly to the decrease of HF-related sympathetic overdrive by ?-blockers.
| S-EPMC3448904 | biostudies-other
Project description:Dysferlin is a membrane-associated protein implicated in muscular dystrophy and vesicle movement and function in muscles. The precise role of dysferlin has been debated, partly because of the mild phenotype in dysferlin-null mice (Dysf). We bred Dysf mice to mice lacking myoferlin (MKO) to generate mice lacking both myoferlin and dysferlin (FER). FER animals displayed progressive muscle damage with myofiber necrosis, internalized nuclei, and, at older ages, chronic remodeling and increasing creatine kinase levels. These changes were most prominent in proximal limb and trunk muscles and were more severe than in Dysf mice. Consistently, FER animals had reduced ad libitum activity. Ultrastructural studies uncovered progressive dilation of the sarcoplasmic reticulum and ectopic and misaligned transverse tubules in FER skeletal muscle. FER muscle, and Dysf- and MKO-null muscle, exuded lipid, and serum glycerol levels were elevated in FER and Dysf mice. Glycerol injection into muscle is known to induce myopathy, and glycerol exposure promotes detachment of transverse tubules from the sarcoplasmic reticulum. Dysf, MKO, and FER muscles were highly susceptible to glycerol exposure in vitro, demonstrating a dysfunctional sarcotubule system, and in vivo glycerol exposure induced severe muscular dystrophy, especially in FER muscle. Together, these findings demonstrate the importance of dysferlin and myoferlin for transverse tubule function and in the genesis of muscular dystrophy.
| S-EPMC3873498 | biostudies-literature
Project description:BACKGROUND:Cardiac dysfunction in failing hearts of human patients and animal models is associated with both microtubule densification and transverse-tubule (T-tubule) remodeling. Our objective was to investigate whether microtubule densification contributes to T-tubule remodeling and excitation-contraction coupling dysfunction in heart disease. METHODS AND RESULTS:In a mouse model of pressure overload-induced cardiomyopathy by transaortic banding, colchicine, a microtubule depolymerizer, significantly ameliorated T-tubule remodeling and cardiac dysfunction. In cultured cardiomyocytes, microtubule depolymerization with nocodazole or colchicine profoundly attenuated T-tubule impairment, whereas microtubule polymerization/stabilization with taxol accelerated T-tubule remodeling. In situ immunofluorescence of heart tissue sections demonstrated significant disorganization of junctophilin-2 (JP2), a protein that bridges the T-tubule and sarcoplasmic reticulum membranes, in transaortic banded hearts as well as in human failing hearts, whereas colchicine injection significantly preserved the distribution of JP2 in transaortic banded hearts. In isolated mouse cardiomyocytes, prolonged culture or treatment with taxol resulted in pronounced redistribution of JP2 from T-tubules to the peripheral plasma membrane, without changing total JP2 expression. Nocodazole treatment antagonized JP2 redistribution. Moreover, overexpression of a dominant-negative mutant of kinesin 1, a microtubule motor protein responsible for anterograde trafficking of proteins, protected against JP2 redistribution and T-tubule remodeling in culture. Finally, nocodazole treatment improved Ca(2+) handling in cultured myocytes by increasing the amplitude of Ca(2+) transients and reducing the frequency of Ca(2+) sparks. CONCLUSION:Our data identify a mechanistic link between microtubule densification and T-tubule remodeling and reveal microtubule-mediated JP2 redistribution as a novel mechanism for T-tubule disruption, loss of excitation-contraction coupling, and heart failure.
| S-EPMC4006305 | biostudies-literature
Project description:BackgroundSGLT2 inhibitors reduce the risk of heart failure (HF) mortality and morbidity, regardless of the presence or absence of diabetes, but the mechanisms underlying this benefit remain unclear. Experiments with nondiabetic HF rats tested the hypothesis that the SGLT2 inhibitor empagliflozin (EMPA) inhibits proximal tubule (PT) NHE3 activity and improves renal salt and water handling.MethodsMale Wistar rats were subjected to myocardial infarction or sham operation. After 4 weeks, rats that developed HF and sham rats were treated with EMPA or untreated for an additional 4 weeks. Immunoblotting and quantitative RT-PCR evaluated SGLT2 and NHE3 expression. Stationary in vivo microperfusion measured PT NHE3 activity.ResultsEMPA-treated HF rats displayed lower serum B-type natriuretic peptide levels and lower right ventricle and lung weight to tibia length than untreated HF rats. Upon saline challenge, the diuretic and natriuretic responses of EMPA-treated HF rats were similar to those of sham rats and were higher than those of untreated HF rats. Additionally, EMPA treatment prevented GFR decline and renal atrophy in HF rats. PT NHE3 activity was higher in HF rats than in sham rats, whereas treatment with EMPA markedly reduced NHE3 activity. Unexpectedly, SGLT2 protein and mRNA abundance were upregulated in the PT of HF rats.ConclusionsPrevention of HF progression by EMPA is associated with reduced PT NHE3 activity, restoration of euvolemia, and preservation of renal mass. Moreover, dysregulation of PT SGLT2 may be involved in the pathophysiology of nondiabetic HF.
| S-EPMC8425656 | biostudies-literature
Project description:Impaired myocardial contractile function is a hallmark of heart failure (HF) which may present under resting conditions and/or during physiological stress. Previous studies reported that high fat feeding in HF is associated with improved myocardial contractile function at baseline. Our goal was to determine whether myocardial function is compromised in response to physiological stress and to evaluate the global gene expression profile of rats fed high dietary fat following infarction. Male Wistar rats underwent ligation or sham surgery and were fed normal (10% kcal fat) (SHAM+NC, HF+NC) or high fat (60% kcal saturated fat) (SHAM+SAT, HF+SAT) for 8 weeks. Myocardial contractile function was assessed using a Millar pressure-volume (PV) conductance catheter at baseline, during inferior vena caval occlusions and dobutamine (DOB) stress. Steady state indices of systolic function, left ventricular (LV)+dP/dtmax, stroke work and maximal power were increased in HF+SAT vs HF+NC; HF+NC were reduced vs SHAM+NC. Preload-recruitable measures of contractility [end systolic PV relationship, maximal elastance, preload recruitable SW and peak+dP/dtmax to end diastolic volume] were decreased in HF+NC but not HF+SAT. β-adrenergic responsiveness (delta-LV+dP/dtmax and delta-cardiac output DOB 0-10 µg•kg-1•min-1) was reduced in HF, but high fat feeding did not further impact contractile reserve in HF. Contractile reserve was reduced by high fat in SHAM+SAT. Microarray gene expression analysis reveals the majority of significantly altered pathways identified to contain multiple gene targets correspond to cell signaling pathways and energy metabolism. These findings suggest that high saturated fat improves myocardial function at rest and during physiological stress in infarcted hearts, but may negatively impact contractile reserve under non-pathological conditions. Furthermore, high fat feeding-induced alterations in gene expression related to energy metabolism and specific signaling pathways reveal promising targets through which high saturated fat potentially mediates cardioprotection in heart failure/LV dysfunction.
2010-09-01 | GSE21021 | GEO