Development of isoproterenol-indueed cardiac hypertrophy

1984 ◽  
Vol 62 (4) ◽  
pp. 384-389 ◽  
Author(s):  
Paul B. Taylor ◽  
Qian Tang
Keyword(s):  
Cardiac Hypertrophy ◽  
Dna Content ◽  
Time Course ◽  
Early Stage ◽  
Phase 1 ◽  
Heart Weight ◽  
Half Time ◽  
Hypertrophic Growth ◽  
Rna Content ◽  
Days Of Therapy

The development of cardiac hypertrophy was studied in adult female Wistar rats following daily subcutaneous injections of isoproterenol (ISO) (0.3 mg/kg body weight). A time course was established for the change in tissue mass, RNA and DNA content, as well as hydroxyproline content. Heart weight increased 44% after 8 days of treatment with a half time of 3.4 days. Ventricular RNA content was elevated 26% after 24 h of a single injection and reached a maximal level following 8 days of therapy. The half time for RNA accumulation was 2.0 days. The total content of hydroxyproline remained stable during the first 2 days of treatment but increased 46% after 4 days of therapy. Ventricular DNA content was unchanged during the early stage (1–4 days) of hypertrophic growth but increased to a new steady-state level 19% above the controls after 8 days of treatment. Intraventricular pressures and coronary flow measures were similar for control and experimental animals following 4 days of developed hypertrophy. However, dP/dt in the ISO-treated hearts was slightly but significantly (P < 0.05) elevated. These data indicate that the adaptive response to ISO shows an early hypertrophic phase (1–4 days) characterized by a substantial increase in RNA content and cardiac mass in the absence of changes in DNA. However, prolonged stimulation (8–12 days) appears to represent a complex integration of both cellular hypertrophy and hyperplasia within the heart.

Regression of isoproterenol-induced cardiac hypertrophy

1984 ◽  
Vol 62 (9) ◽  
pp. 1141-1146 ◽  
Author(s):  
Qian Tang ◽  
Paul B. Taylor
Keyword(s):  
Cardiac Hypertrophy ◽  
Recovery Period ◽  
Control Level ◽  
Weight Ratio ◽  
Heart Weight ◽  
Half Time ◽  
Body Weight Ratio ◽  
Subcutaneous Injections ◽  
Rna Content ◽  
Female Wistar Rats

Cardiac hypertrophy was induced in adult female Wistar rats after 8 days of daily subcutaneous injections of isoproterenol (ISO). Regression from hypertrophy was studied following 1, 2, 4, 8, 12, and 20 days of ISO withdrawal. After 8 days of treatment cardiac mass increased 40%. Following ISO withdrawal, ventricular regression occurred during the first 8 days. After 12–20 days of recovery, a new steady-state heart weight to body weight ratio was established that was 12–13% above the controls. The half-time recovery for heart weight was 3.8 days. Ventricular RNA content was stimulated 76% after 8 days of ISO-induced hypertrophy. During regression RNA content decreased rapidly during the first 8 days with a half-time of 3.4 days. Following 20 days of recovery ventricular RNA was still 31% above the controls. However, myocyte RNA was stimulated 86% following 8 days of ISO treatment and returned to control level after 12 days of regression. Myocardial DNA was increased 23% in the hypertrophied hearts and did not change during the recovery period. Hydroxyproline was increased in the ISO-treated hearts and decreased only slightly during the recovery interval. These data indicate that ISO-induced hypertrophy was reversible while ventricular RNA content only partially recovered. Nevertheless, myocyte RNA showed a large stimulation that was completely reversible at least after 12 days of recovery.

Abstract 20118: Defining the Sufficiency of Atg7 to Suppress Phenylephrine-induced Cardiac Hypertrophy

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Marcus Tjeerdsma ◽  
Levi Froke ◽  
Jessica Freeling ◽  
Scott Pattison
Keyword(s):  
Body Weight ◽  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Heart Weight ◽  
Autophagic Flux ◽  
Specific Expression ◽  
Hypertrophic Growth ◽  
Fractional Shortening

Introduction: Macroautophagy is a process of bulk protein degradation. Our prior work showed that Atg7 expression is sufficient to induce autophagic flux in vitro and in vivo . When Atg7 was co-expressed with CryAB R120G in the heart, cardiac hypertrophy was blunted in heart weight/body weight ratios and fetal gene expression markers. To determine if Atg7 expression is sufficient to limit hypertrophic growth in another model, we tested the effects of Atg7 overexpression with phenylephrine-induced hypertrophy both in vitro and in vivo . Hypothesis: Atg7 will blunt the hypertrophic effects of phenylephrine. Methods: Rat neonatal cardiomyocytes were infected with adenoviruses expressing either LacZ or Atg7 and treated with phenylephrine to induce cardiomyocytes hypertrophy. Osmotic pumps were surgically implanted into control mice and mice with cardiac-specific expression of Atg7 to infuse phenylephrine (PE) or vehicle (saline) for four weeks. Results: PE treatment significantly increased neonatal cardiomyocyte areas in LacZ-expressing cells, while Atg7-expressing cardiomyocytes showed no growth. In mice, all genotypes responded to PE treatment with significantly increased heart weight/body weight ratios and increased fiber size. However, Atg7-expressing hearts differed significantly from control hearts in normalized heart mass following PE delivery. Vehicle treated Atg7-expressing hearts had 17% smaller myofiber cross-sectional areas than those from control genotypes and had a reduced hypertrophic response to PE, relative to controls. Echocardiography showed that Atg7-expressing hearts had significantly elevated cardiac function (% fractional shortening) prior to and throughout the experiment over control hearts (33% vs. 29%). PE significantly increased fractional shortening) from 29% to 36% in control hearts, but failed to significantly elevate cardiac function in Atg7-expressing hearts further (33% vs 35%). Additional assays are underway to understand the Atg7-dependent adaptations to PE. Conclusion: Atg7 expression yields modestly smaller hearts with enhanced cardiac function which may protect them from hypertrophic stresses like phenylephrine.

Efficiency and capacity of protein synthesis are increased in pressure overload cardiac hypertrophy

1988 ◽  
Vol 255 (2) ◽  
pp. H325-H328 ◽  
Author(s):  
R. Nagai ◽  
R. B. Low ◽  
W. S. Stirewalt ◽  
N. R. Alpert ◽  
R. Z. Litten
Keyword(s):  
Protein Synthesis ◽  
Pulmonary Artery ◽  
Cardiac Hypertrophy ◽  
Right Ventricle ◽  
Pressure Overload ◽  
Heart Weight ◽  
Rna Content ◽  
The Right ◽  
Pulmonary Artery Constriction

We measured the rate of protein synthesis and total RNA content in the right ventricle (RV) at day 2 and day 4 after pulmonary artery constriction to determine the contributions of changes in capacity and efficiency of in vivo protein synthesis to pressure overload (PO) cardiac hypertrophy. A significant increase in the proportion of RV weight to total heart weight was observed at day 2 and day 4 when compared with untreated controls. The rate of protein synthesis was significantly higher at day 2 post-PO (0.31 +/- 0.06 day-1 or 30 +/- 5 mg.g RV-1.day-1, means +/- SD, P less than 0.05) as well as at day 4 (0.25 +/- 0.05 day-1 or 28 +/- 9 mg.g RV-1.day-1, P less than 0.05) than for untreated rabbits (0.15 +/- 0.03 day-1 or 17 +/- 4 mg.g RV-1.day-1). RNA content was significantly higher at day 2 (1.47 +/- 0.17 mg/g RV, P less than 0.05) than in controls (1.16 +/- 0.14 mg/g RV), whereas there was a slight but nonsignificant increase at day 4 (1.36 +/- 0.21 mg/g RV, P less than 0.1). The efficiency of protein synthesis (synthesis/RNA) per gram RV was significantly increased both at day 2 (20.5 +/- 2.2 g protein.g RNA-1.day-1, P less than 0.05) and day 4 (19.8 +/- 3.5 g protein.g RNA-1.day-1, P less than 0.05) compared with control (14.6 +/- 2.3 g protein.g RNA-1.day-1). The increase in efficiency appeared to be caused by pressure overload itself based on a comparison of 0-4 day data vs. data obtained from sham animals (P less than 0.05).

Abstract 084: Dkk1 Knock out Leads To Augmentation Of Cardiac Hypertrophy Following Aortic Banding

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Johannes H Riffel ◽  
Elmar Bernhold ◽  
Marco Hagenmueller ◽  
Min Zhang ◽  
Christof Niehrs ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Wnt Signaling ◽  
Histological Evaluation ◽  
Heart Weight ◽  
Sham Operation ◽  
Aortic Banding ◽  
Knock Out ◽  
Hypertrophic Growth ◽  
Knock Out Mice

Background: Myocardial hypertrophy is an important risk factor for cardiac morbidity and mortality. In the normal adult heart, Wnt signaling remains quiescent. However, recent studies have demonstrated reactivation of Wnt signaling in hypertrophic growth of cardiomyocytes. Under such conditions Wnt signaling may be beneficial or maladaptive depending on the context. The Wnt coreceptors LRP5 and LRP6 are important for signal transmission via the β-catenin pathway and are negatively regulated by Dkk1, a member of a small family of secretory proteins. Dkk1 binds to LRP6 and thereby acts as a Wnt antagonist. In our study we investigated the cardiovascular phenotype of Dkk1 knock-out mice following aortic banding. Study Design and Results: Dkk1 (+/-) knock-out mice were subjected to aortic banding (AB) or sham operation. After 4 weeks echocardiographic and invasive measurements were performed. After that the mice were euthanized, heart weight was measured and myocardial samples were snap frozen for biochemical measurements or fixed in formalin for further histological evaluation. Under baseline conditions there were no differences in cardiomyocyte size, heart weight and cardiac function in Dkk1 knock-out animals compared to wild type animals. 4 weeks after aortic banding we observed a significant increase in heart weight/body weight ratio in Dkk1 knock out animals compared to the control group (7.3 ± 0.3 mg/g vs. 6.4 ± 0.3 mg/g, p < 0.05). Furthermore cardiomyocyte size was highly elevated in Dkk1 knock out mice compared to control animals, suggesting an augmentation in cardiac hypertrophy. Transcription levels of the pro-hypertrophic markers atrial natriuretic factor (ANF) and beta-MHC were increased in Dkk1 knock out animals. Interestingly echocardiographic data revealed an aggravation of cardiac function in Dkk1 knock out mice following aortic banding (Ejection fraction (EF): 62 ± 3 % vs. 74 ± 1 %, p < 0.05). Summary: Our findings suggest that Dkk1 knock out aggravates cardiac hypertrophy following aortic banding. The underlying molecular mechanisms remain to be further explored.

Diazoxide Modulates Cardiac Hypertrophy by Targeting H2O2 Generation and Mitochondrial Superoxide Dismutase Activity

2020 ◽  
Vol 13 (1) ◽  
pp. 76-83
Author(s):  
Aline Maria Brito Lucas ◽  
Joana Varlla de Lacerda Alexandre ◽  
Maria Thalyne Silva Araújo ◽  
Cicera Edna Barbosa David ◽  
Yuana Ivia Ponte Viana ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Superoxide Dismutase ◽  
Cardiac Hypertrophy ◽  
Superoxide Dismutase Activity ◽  
Heart Weight ◽  
Pharmacological Intervention ◽  
Wall Thickening ◽  
H2o2 Production ◽  
Mitochondrial Superoxide ◽  
Mitochondrial Superoxide Dismutase

Background: Cardiac hypertrophy involves marked wall thickening or chamber enlargement. If sustained, this condition will lead to dysfunctional mitochondria and oxidative stress. Mitochondria have ATP-sensitive K+ channels (mitoKATP) in the inner membrane that modulate the redox status of the cell. Objective: We investigated the in vivo effects of mitoKATP opening on oxidative stress in isoproterenol- induced cardiac hypertrophy. Methods: Cardiac hypertrophy was induced in Swiss mice treated intraperitoneally with isoproterenol (ISO - 30 mg/kg/day) for 8 days. From day 4, diazoxide (DZX - 5 mg/kg/day) was used in order to open mitoKATP (a clinically relevant therapy scheme) and 5-hydroxydecanoate (5HD - 5 mg/kg/day) or glibenclamide (GLI - 3 mg/kg/day) were used as mitoKATP blockers. Results: Isoproterenol-treated mice had elevated heart weight/tibia length ratios (HW/TL). Additionally, hypertrophic hearts had elevated levels of carbonylated proteins and Thiobarbituric Acid Reactive Substances (TBARS), markers of protein and lipid oxidation. In contrast, mitoKATP opening with DZX avoided ISO effects on gross hypertrophic markers (HW/TL), carbonylated proteins and TBARS, in a manner reversed by 5HD and GLI. Moreover, DZX improved mitochondrial superoxide dismutase activity. This effect was also blocked by 5HD and GLI. Additionally, ex vivo treatment of isoproterenol- induced hypertrophic cardiac tissue with DZX decreased H2O2 production in a manner sensitive to 5HD, indicating that this drug also acutely avoids oxidative stress. Conclusion: Our results suggest that diazoxide blocks oxidative stress and reverses cardiac hypertrophy. This pharmacological intervention could be a potential therapeutic strategy to prevent oxidative stress associated with cardiac hypertrophy.

scholarly journals KLK11 promotes the activation of mTOR and protein synthesis to facilitate cardiac hypertrophy

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Yi Wang ◽  
Hongjuan Liao ◽  
Yueheng Wang ◽  
Jinlin Zhou ◽  
Feng Wang ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Western Blot ◽  
Real Time ◽  
Real Time Pcr ◽  
Mtor Signaling ◽  
Heart Weight ◽  
Cardiomyocyte Hypertrophy ◽  
Quantitative Real Time Pcr

Abstract Background Cardiovascular diseases have become the leading cause of death worldwide, and cardiac hypertrophy is the core mechanism underlying cardiac defect and heart failure. However, the underlying mechanisms of cardiac hypertrophy are not fully understood. Here we investigated the roles of Kallikrein 11 (KLK11) in cardiac hypertrophy. Methods Human and mouse hypertrophic heart tissues were used to determine the expression of KLK11 with quantitative real-time PCR and western blot. Mouse cardiac hypertrophy was induced by transverse aortic constriction (TAC), and cardiomyocyte hypertrophy was induced by angiotensin II. Cardiac function was analyzed by echocardiography. The signaling pathway was analyzed by western blot. Protein synthesis was monitored by the incorporation of [3H]-leucine. Gene expression was analyzed by quantitative real-time PCR. Results The mRNA and protein levels of KLK11 were upregulated in human hypertrophic hearts. We also induced cardiac hypertrophy in mice and observed the upregulation of KLK11 in hypertrophic hearts. Our in vitro experiments demonstrated that KLK11 overexpression promoted whereas KLK11 knockdown repressed cardiomyocytes hypertrophy induced by angiotensin II, as evidenced by cardiomyocyte size and the expression of hypertrophy-related fetal genes. Besides, we knocked down KLK11 expression in mouse hearts with adeno-associated virus 9. Knockdown of KLK11 in mouse hearts inhibited TAC-induced decline in fraction shortening and ejection fraction, reduced the increase in heart weight, cardiomyocyte size, and expression of hypertrophic fetal genes. We also observed that KLK11 promoted protein synthesis, the key feature of cardiomyocyte hypertrophy, by regulating the pivotal machines S6K1 and 4EBP1. Mechanism study demonstrated that KLK11 promoted the activation of AKT-mTOR signaling to promote S6K1 and 4EBP1 pathway and protein synthesis. Repression of mTOR with rapamycin blocked the effects of KLK11 on S6K1 and 4EBP1 as well as protein synthesis. Besides, rapamycin treatment blocked the roles of KLK11 in the regulation of cardiomyocyte hypertrophy. Conclusions Our findings demonstrated that KLK11 promoted cardiomyocyte hypertrophy by activating AKT-mTOR signaling to promote protein synthesis.

scholarly journals EEG Fractal Analysis Reflects Brain Impairment after Stroke

Entropy ◽  
2021 ◽  
Vol 23 (5) ◽  
pp. 592
Author(s):  
Maria Rubega ◽  
Emanuela Formaggio ◽  
Franco Molteni ◽  
Eleonora Guanziroli ◽  
Roberto Di Marco ◽  
...  
Keyword(s):  
Early Stage ◽  
Brain Activity ◽  
Phase 1 ◽  
Behavioral Changes ◽  
Stroke Survivors ◽  
Eeg Signals ◽  
Novel Treatments ◽  
Fractal Measures ◽  
Underlying Mechanisms ◽  
Random Fluctuations

Stroke is the commonest cause of disability. Novel treatments require an improved understanding of the underlying mechanisms of recovery. Fractal approaches have demonstrated that a single metric can describe the complexity of seemingly random fluctuations of physiological signals. We hypothesize that fractal algorithms applied to electroencephalographic (EEG) signals may track brain impairment after stroke. Sixteen stroke survivors were studied in the hyperacute (<48 h) and in the acute phase (∼1 week after stroke), and 35 stroke survivors during the early subacute phase (from 8 days to 32 days and after ∼2 months after stroke): We compared resting-state EEG fractal changes using fractal measures (i.e., Higuchi Index, Tortuosity) with 11 healthy controls. Both Higuchi index and Tortuosity values were significantly lower after a stroke throughout the acute and early subacute stage compared to healthy subjects, reflecting a brain activity which is significantly less complex. These indices may be promising metrics to track behavioral changes in the very early stage after stroke. Our findings might contribute to the neurorehabilitation quest in identifying reliable biomarkers for a better tailoring of rehabilitation pathways.

scholarly journals Effect of mesenchymal stromal cell infusions on lung function in COPD patients with high CRP levels

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Daniel J. Weiss ◽  
Karen Segal ◽  
Richard Casaburi ◽  
Jack Hayes ◽  
Donald Tashkin
Keyword(s):  
Lung Function ◽  
Time Course ◽  
Inflammatory Marker ◽  
Controlled Trial ◽  
Phase 1 ◽  
Forced Expiratory Volume ◽  
Allogeneic Mscs ◽  
Copd Exacerbations ◽  
Copd Patients ◽  
Patient Reported

Abstract Background We previously reported a Phase 1/2 randomized placebo-controlled trial of systemic administration of bone marrow-derived allogeneic MSCs (remestemcel-L) in COPD. While safety profile was good, no functional efficacy was observed. However, in view of growing recognition of effects of inflammatory environments on MSC actions we conducted a post-hoc analysis with stratification by baseline levels of a circulating inflammatory marker, C-reactive protein (CRP) to determine the effects of MSC administration in COPD patients with varying circulating CRP levels. Methods Time course of lung function, exercise performance, patient reported responses, and exacerbation frequency following four monthly infusions of remestemcel-L vs. placebo were re-assessed in subgroups based on baseline circulating CRP levels. Results In COPD patients with baseline CRP ≥ 4 mg/L, compared to COPD patients receiving placebo (N = 17), those treated with remestemcel-L (N = 12), demonstrated significant improvements from baseline in forced expiratory volume in one second, forced vital capacity, and six minute walk distance at 120 days with treatment differences evident as early as 10 days after the first infusion. Significant although smaller benefits were also detected in those with CRP levels ≥ 2 or ≥ 3 mg/L. These improvements persisted variably over the 2-year observational period. No significant benefits were observed in patient reported responses or number of COPD exacerbations between treatment groups. Conclusion In an inflammatory environment, defined by elevated circulating CRP, remestemcel-L administration yielded at least transient meaningful pulmonary and functional improvements. These findings warrant further investigation of potential MSC-based therapies in COPD and other inflammatory pulmonary diseases. Trial registration: Clinicaltrials.gov NCT00683722.

scholarly journals Cognitive dysfunction in amyotrophic lateral sclerosis: can we predict it?

2021 ◽  
Author(s):  
Fabiola De Marchi ◽  
◽  
Claudia Carrarini ◽  
Antonio De Martino ◽  
Luca Diamanti ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Time Course ◽  
Neurodegenerative Disorder ◽  
Early Stage ◽  
Multisystem Disorder ◽  
Behavioral Impairment ◽  
Behavioral Impairments ◽  
Als Patients ◽  
Disease Stages ◽  
Lateral Sclerosis

Abstract Background and aim Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by the degeneration of both upper and lower motoneurons in the brain and spinal cord leading to motor and extra-motor symptoms. Although traditionally considered a pure motor disease, recent evidences suggest that ALS is a multisystem disorder. Neuropsychological alterations, in fact, are observed in more than 50% of patients: while executive dysfunctions have been firstly identified, alterations in verbal fluency, behavior, and pragmatic and social cognition have also been described. Detecting and monitoring ALS cognitive and behavioral impairment even at early disease stages is likely to have staging and prognostic implications, and it may impact the enrollment in future clinical trials. During the last 10 years, humoral, radiological, neurophysiological, and genetic biomarkers have been reported in ALS, and some of them seem to potentially correlate to cognitive and behavioral impairment of patients. In this review, we sought to give an up-to-date state of the art of neuropsychological alterations in ALS: we will describe tests used to detect cognitive and behavioral impairment, and we will focus on promising non-invasive biomarkers to detect pre-clinical cognitive decline. Conclusions To date, the research on humoral, radiological, neurophysiological, and genetic correlates of neuropsychological alterations is at the early stage, and no conclusive longitudinal data have been published. Further and longitudinal studies on easily accessible and quantifiable biomarkers are needed to clarify the time course and the evolution of cognitive and behavioral impairments of ALS patients.

Synthesis and turnover of proteins and mRNA in germinating wheat embryos

1982 ◽  
Vol 60 (3) ◽  
pp. 389-397 ◽  
Author(s):  
Zbyszko F. Grzelczak ◽  
Mark H. Sattolo ◽  
Linda K. Hanley-Bowdoin ◽  
Theresa D. Kennedy ◽  
Byron G. Lane
Keyword(s):  
Growth Phase ◽  
Time Course ◽  
Phase 1 ◽  
Major Product ◽  
Lag Phase ◽  
Wheat Embryo ◽  
Phase Development ◽  
Wheat Embryos

The most prominent methionine-labeled protein made when cell-free systems are programmed with bulk mRNA from dry wheat embryos has been identified with what may be the most abundant protein in dry wheat embryos. The protein has been brought to purity and has a distinctive amino acid composition, Gly and Glx accounting for almost 40% of the total amino acids. Designated E because of its conspicuous association with early imbibition of dry wheat embryos, the protein and its mRNA are abundant during the "early" phase (0–1 h) of postimbibition development, and easily detected during "lag" phase (1–5 h), but they are almost totally degraded soon after entry into the "growth" phase of development, by about 10 h postimbibition.The most prominent methionine-labeled protein peculiar to the cell-free translational capacity of bulk mRNA from "growth" phase embryos is not detected as a product of in vivo synthesis. Its electrophoretic properties and its time course of emergence, after 5 h postimbibition development, suggest that this major product of cell-free synthesis may be an in vitro counterpart to a prominent methionine-labeled protein made only in vivo, by "growth" phase embryos. Designated G because of its conspicuous association with "growth" phase development, the cell-free product does not comigrate with any prominent dye-stained band in electrophoretic distributions of wheat proteins. The suspected cellular counterpart to G, also, does not comigrate with a prominent dye-stained wheat protein during electrophoresis, and although found in particulate as well as soluble fractions of wheat embryo homogenates it is not concentrated in either nuclei or mitochondria, as isolated.

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