Altered hemodynamics in transgenic mice harboring mutant tropomyosin linked to hypertrophic cardiomyopathy

2000 ◽  
Vol 279 (5) ◽  
pp. H2414-H2423 ◽  
Author(s):  
Christian C. Evans ◽  
James R. Pena ◽  
Ronald M. Phillips ◽  
Mariappan Muthuchamy ◽  
David F. Wieczorek ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Protein Kinase ◽  
Left Ventricular ◽  
Familial Hypertrophic Cardiomyopathy ◽  
Fiber Bundles ◽  
Papillary Muscles ◽  
Adrenergic Stimulation ◽  
Skinned Fiber Bundles ◽  
Force Relationship ◽  
Kinase A

We used transgenic (TG) mice overexpressing mutant α-tropomyosin [α-Tm(Asp175Asn)], linked to familial hypertrophic cardiomyopathy (FHC), to test the hypothesis that this mutation impairs cardiac function by altering the sensitivity of myofilaments to Ca2+. Left ventricular (LV) pressure was measured in anesthetized nontransgenic (NTG) and TG mice. In control conditions, LV relaxation was 6,970 ± 297 mmHg/s in NTG and 5,624 ± 392 mmHg/s in TG mice ( P < 0.05). During β-adrenergic stimulation, the rate of relaxation increased to 8,411 ± 323 mmHg/s in NTG and to 6,080 ± 413 mmHg/s in TG mice ( P < 0.05). We measured the pCa-force relationship (pCa = −log [Ca2+]) in skinned fiber bundles from LV papillary muscles of NTG and TG hearts. In control conditions, the Ca2+ concentration producing 50% maximal force (pCa50) was 5.77 ± 0.02 in NTG and 5.84 ± 0.01 in TG myofilament bundles ( P < 0.05). After protein kinase A-dependent phosphorylation, the pCa50 was 5.71 ± 0.01 in NTG and 5.77 ± 0.02 in TG myofilament bundles ( P < 0.05). Our results indicate that mutant α-Tm(Asp175Asn) increases myofilament Ca2+-sensitivity, which results in decreased relaxation rate and blunted response to β-adrenergic stimulation.

scholarly journals Temporal and mutation-specific alterations in Ca2+ homeostasis differentially determine the progression of cTnT-related cardiomyopathies in murine models

2009 ◽  
Vol 297 (2) ◽  
pp. H614-H626 ◽  
Author(s):  
Pia J. Guinto ◽  
Todd E. Haim ◽  
Candice C. Dowell-Martino ◽  
Nathaniel Sibinga ◽  
Jil C. Tardiff
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Ventricular Myocytes ◽  
Troponin T ◽  
Early Time ◽  
Left Ventricular ◽  
Familial Hypertrophic Cardiomyopathy ◽  
Compensatory Mechanism ◽  
Missense Mutations ◽  
Tail Domain ◽  
Cellular Mechanics

Naturally occurring mutations in cardiac troponin T (cTnT) result in a clinical subset of familial hypertrophic cardiomyopathy. To determine the mechanistic links between thin-filament mutations and cardiovascular phenotypes, we have generated and characterized several transgenic mouse models carrying cTnT mutations. We address two central questions regarding the previously observed changes in myocellular mechanics and Ca2+ homeostasis: 1) are they characteristic of all severe cTnT mutations, and 2) are they primary (early) or secondary (late) components of the myocellular response? Adult left ventricular myocytes were isolated from 2- and 6-mo-old transgenic mice carrying missense mutations at residue 92, flanking the TNT1 NH2-terminal tail domain. Results from R92L and R92W myocytes showed mutation-specific alterations in contraction and relaxation indexes at 2 mo with improvements by 6 mo. Alterations in Ca2+ kinetics remained consistent with mechanical data in which R92L and R92W exhibited severe diastolic impairments at the early time point that improved with increasing age. A normal regulation of Ca2+ kinetics in the context of an altered baseline cTnI phosphorylation suggested a pathogenic mechanism at the myofilament level taking precedence for R92L. The quantitation of Ca2+-handling proteins in R92W mice revealed a synergistic compensatory mechanism involving an increased Ser16 and Thr17 phosphorylation of phospholamban, contributing to the temporal onset of improved cellular mechanics and Ca2+ homeostasis. Therefore, independent cTnT mutations in the TNT1 domain result in primary mutation-specific effects and a differential temporal onset of altered myocellular mechanics, Ca2+ kinetics, and Ca2+ homeostasis, complex mechanisms which may contribute to the clinical variability in cTnT-related familial hypertrophic cardiomyopathy mutations.

scholarly journals Discrete effects of A57G-myosin essential light chain mutation associated with familial hypertrophic cardiomyopathy

2013 ◽  
Vol 305 (4) ◽  
pp. H575-H589 ◽  
Author(s):  
Katarzyna Kazmierczak ◽  
Ellena C. Paulino ◽  
Wenrui Huang ◽  
Priya Muthu ◽  
Jingsheng Liang ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Light Chain ◽  
Left Ventricular ◽  
Compensatory Hypertrophy ◽  
Familial Hypertrophic Cardiomyopathy ◽  
Heart Weight ◽  
Myocardial Stiffness ◽  
Essential Light Chain

The functional consequences of the familial hypertrophic cardiomyopathy A57G (alanine-to-glycine) mutation in the myosin ventricular essential light chain (ELC) were assessed in vitro and in vivo using previously generated transgenic (Tg) mice expressing A57G-ELC mutant vs. wild-type (WT) of human cardiac ELC and in recombinant A57G- or WT-protein-exchanged porcine cardiac muscle strips. Compared with the Tg-WT, there was a significant increase in the Ca2+ sensitivity of force (ΔpCa50 ≅ 0.1) and an ∼1.3-fold decrease in maximal force per cross section of muscle observed in the mutant preparations. In addition, a significant increase in passive tension in response to stretch was monitored in Tg-A57G vs. Tg-WT strips indicating a mutation-induced myocardial stiffness. Consistently, the hearts of Tg-A57G mice demonstrated a high level of fibrosis and hypertrophy manifested by increased heart weight-to-body weight ratios and a decreased number of nuclei indicating an increase in the two-dimensional size of Tg-A57G vs. Tg-WT myocytes. Echocardiography examination showed a phenotype of eccentric hypertrophy in Tg-A57G mice, enhanced left ventricular (LV) cavity dimension without changes in LV posterior/anterior wall thickness. Invasive hemodynamics data revealed significantly increased end-systolic elastance, defined by the slope of the pressure-volume relationship, indicating a mutation-induced increase in cardiac contractility. Our results suggest that the A57G allele causes disease by means of a discrete modulation of myofilament function, increased Ca2+ sensitivity, and decreased maximal tension followed by compensatory hypertrophy and enhanced contractility. These and other contributing factors such as increased myocardial stiffness and fibrosis most likely activate cardiomyopathic signaling pathways leading to pathologic cardiac remodeling.

scholarly journals Effects of nicotine administration in a mouse model of familial hypertrophic cardiomyopathy, α-tropomyosin D175N

2011 ◽  
Vol 301 (4) ◽  
pp. H1646-H1655 ◽  
Author(s):  
Robert D. Gaffin ◽  
Shamim A. K. Chowdhury ◽  
Marco S. L. Alves ◽  
Fernando A. L. Dias ◽  
Cibele T. D. Ribeiro ◽  
...  
Keyword(s):  
Heart Rate ◽  
Hypertrophic Cardiomyopathy ◽  
Mouse Model ◽  
Troponin I ◽  
Left Ventricular ◽  
Familial Hypertrophic Cardiomyopathy ◽  
Maximal Rate ◽  
Western Blots ◽  
Nicotine Administration ◽  
Acute And Chronic Effects

The effects of nicotine (NIC) on normal hearts are fairly well established, yet its effects on hearts displaying familial hypertrophic cardiomyopathy have not been tested. We studied both the acute and chronic effects of NIC on a transgenic (TG) mouse model of FHC caused by a mutation in α-tropomyosin (Tm; i.e., α-Tm D175N TG, or Tm175). For acute effects, intravenously injected NIC increased heart rate, left ventricular (LV) pressure, and the maximal rate of LV pressure increase (+dP/d t) in non-TG (NTG) and Tm175 mice; however, Tm175 showed a significantly smaller increase in the maximal rate of LV pressure decrease (−dP/ dt) compared with NTGs. Western blots revealed phosphorylation of phospholamban Ser16 and Thr17 residue increased in NTG mice following NIC injection but not in Tm175 mice. In contrast, phosphorylation of troponin I at serine residues 23 and 24 increased equally in both NTG and Tm175. Thus the attenuated increase in relaxation in Tm175 mice following acute NIC appears to result primarily from attenuated phospholamban phosphorylation. Chronic NIC administration (equivalent to smoking 2 packs of cigarettes/day for 4 mo) also increased +dP/dt in NTG and Tm175 mice compared with chronic saline. However, chronic NIC had little effect on heart rate, LV pressure, −dP/d t, LV wall and chamber dimensions, or collagen content for either group of mice.

cAMP-positive regulation of angiotensinogen gene expression and protein secretion in rat adipose tissue

2004 ◽  
Vol 286 (3) ◽  
pp. E434-E438 ◽  
Author(s):  
Valérie Serazin ◽  
Marie-Noelle Dieudonné ◽  
Mireille Morot ◽  
Philippe de Mazancourt ◽  
Yves Giudicelli
Keyword(s):  
Adipose Tissue ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
Protein Secretion ◽  
Intracellular Camp ◽  
Pathological State ◽  
Mrna Levels ◽  
Adrenergic Stimulation ◽  
Rat Adipose Tissue ◽  
Kinase A

The adipose renin-angiotensin system (RAS) has been assigned to participate in the control of adipose tissue development and in the pathogenesis of obesity-related hypertension. In adipose cells, the biological responses to β-adrenergic stimulation are mediated by an increase in intracellular cAMP. Because cAMP is known to promote adipogenesis and because an association exists between body fat mass, hypertension, and increased sympathetic stimulation, we examined the influence of cAMP on angiotensinogen (ATG) expression and secretion in rat adipose tissue. Exposure of primary cultured differentiated preadipocytes to the cAMP analog 8-bromoadenosine 3′,5′-cyclic monophosphate (8-BrcAMP) or cAMP-stimulating agents (forskolin and IBMX) results in a significant increase in ATG mRNA levels. In adipose tissue fragments, 8-BrcAMP also increases ATG mRNA levels and protein secretion, but not in the presence of the protein kinase A inhibitor H89. The addition of isoproterenol, known to stimulate the synthesis of intracellular cAMP via β-adrenoreceptors, had the same stimulatory effect on ATG expression and secretion. These results indicate that cAMP in vitro upregulates ATG expression and secretion in rat adipose tissue via the protein kinase A-dependent pathway. Further studies are required to determine whether this regulatory pathway is activated in human obesity, where increased sympathetic tone is frequently observed, and to elucidate the importance of adipose ATG to the elevated blood pressure observed in this pathological state.

scholarly journals Diagnostic opportunities of magnetic resonant imagingmri of heart in differential diagnosis of phenotypical forms of hypertrophic cardiomyopathy

2021 ◽  
Vol 11 (4) ◽  
pp. 44-51
Author(s):  
A. A. Malov ◽  
R. K. Dzhordzhikiya ◽  
A. I. Abushayev
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Mitral Valve ◽  
Short Pulse ◽  
Interventricular Septum ◽  
Left Ventricular ◽  
Papillary Muscles ◽  
Post Contrast ◽  
Lv Remodeling ◽  
Myocardial Crypts ◽  
Tissue Characteristics

Introduction. Phenotype variants of left ventricular (LV) remodeling in patients with hypertrophic cardiomyopathy (HCM) are often associated with abnormalities of the mitral valve (MV), myocardiumstructure, contributing to the development of medium and/or subaortic obstruction. Itcauses the detail visualization of morphological obstruction substrates, tissue characteristics.Aim. To evaluate the possibilities of magnetic resonance imaging (MRI) in the diagnosis of various forms of HCM and combined abnormalities.Materials and methods. 75 patients with suspected HCM were examined. For verification, all patients underwentMRI using protocol: short-pulse T1w-TSE/ T2w-TSE (STIR), gradient echo in cine (CINE), T1-weighted post-contrast images (Inversion Recovery IR-MDE). Results. Patients classified into 4 types according to the anatomical principle (Wiggle E.D. et al., 1985). In addition to the most frequent forms affecting the interventricular septum (IVS) — 64 patients, unusual forms covering the apical zones and papillary muscles — 11 patients. The majority of patients were diagnosed with abnormalities of MV, divided into abnormalities of the number and position of papillary muscles, as well as the ratio of chords and muscles. Myocardial crypts were diagnosed in 12 patients, some combined with areas of non-compact myocardium. Post-contrast visualization using the delayed contrast technique allowed differentiating HCM with accumulation diseases, excluding cavity thrombosis, and evaluating the severity of myocardial fibrosis.Conclusions. MRI allows to estimate in details anatomic picture of LV remodeling, to diagnose features of the mitral valve, tissue characteristics that allows to stratify risk of sudden death, classify the HCM phenotype form and to determine the volume of surgical intervention.

Positive and negative effects of nitric oxide on Ca2+ sparks: influence of β-adrenergic stimulation

2001 ◽  
Vol 281 (6) ◽  
pp. H2295-H2303 ◽  
Author(s):  
Mark T. Ziolo ◽  
Hideki Katoh ◽  
Donald M. Bers
Keyword(s):  
Nitric Oxide ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
Ventricular Myocytes ◽  
Cardiac Contractility ◽  
Adrenergic Stimulation ◽  
High Concentration ◽  
Negative Effects ◽  
Dual Effect ◽  
Kinase A

Nitric oxide (NO) can have a positive or negative effect on cardiac contractility and the ryanodine receptor (RyR). This dual effect has been explained as being dependent on the concentration of NO. We find that cellular RyR response to NO is also dependent on the degree of β-adrenergic stimulation, and thus the state of protein kinase A activation. Ca2+ spark frequency (CaSpF) in rat ventricular myocytes was used as an index of resting RyR activity. CaSpF response to β-adrenergic stimulation was used as an index of protein kinase A activation. High concentration of isoproterenol, a β-adrenergic agonist, caused a large increase in CaSpF; addition of NO (spermine NONOate, 300 μM) then caused a decrease in CaSpF. Low concentration of isoproterenol produced only a slight increase in CaSpF, but the same NO concentration now caused a large increase in CaSpF. A dual effect was also observed in twitch. Thus the net direction of the effects of NO on RyR activity and Ca2+transients (directly or by alteration of sarcoplasmic reticulum Ca2+ load) can be reversed, depending on the ambient level of β-adrenergic activation.

Phosphorylation of the salivary Na+-K+-2Cl− cotransporter

2002 ◽  
Vol 282 (4) ◽  
pp. C817-C823 ◽  
Author(s):  
Kinji Kurihara ◽  
Nobuo Nakanishi ◽  
Marilyn L. Moore-Hoon ◽  
R. James Turner
Keyword(s):  
Protein Kinase ◽  
Kinase Activity ◽  
Acinar Cells ◽  
Good Evidence ◽  
Protein Kinase Activity ◽  
Adrenergic Stimulation ◽  
Parotid Acinar Cells ◽  
Rat Parotid ◽  
Phosphopeptide Mapping ◽  
Kinase A

We studied the phosphorylation of the secretory Na+-K+-2Cl− cotransporter (NKCC1) in rat parotid acinar cells. We have previously shown that NKCC1 activity in these cells is dramatically upregulated in response to β-adrenergic stimulation and that this upregulation correlates with NKCC1 phosphorylation, possibly due to protein kinase A (PKA). We show here that when ATP is added to purified acinar basolateral membranes (BLM), NKCC1 is phosphorylated as a result of membrane-associated protein kinase activity. Additional NKCC1 phosphorylation is seen when PKA is added to BLMs, but our data indicate that this is due to an effect of PKA on endogenous membrane kinase or phosphatase activities, rather than its direct phosphorylation of NKCC1. Also, phosphopeptide mapping demonstrates that these phosphorylations do not take place at the site associated with the upregulation of NKCC1 by β-adrenergic stimulation. However, this upregulatory phosphorylation can be mimicked by the addition of cAMP to permeabilized acini, and this effect can be blocked by a specific PKA inhibitor. These latter results provide good evidence that PKA is indeed involved in the upregulatory phosphorylation of NKCC1 and suggest that an additional factor present in the acinar cell but absent from isolated membranes is required to bring about the phosphorylation.

Hypertrophic cardiomyopathy

2018 ◽  
pp. 243-252
Author(s):  
Carmen Chan ◽  
Martin S Maron
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Wall Thickness ◽  
Systolic Dysfunction ◽  
Management Strategies ◽  
Left Ventricular ◽  
Papillary Muscles ◽  
Common Cause ◽  
Contrast Enhanced ◽  
Increased Risk

Hypertrophic cardiomyopathy (HCM) is a genetic cardiomyopathy and the most common cause of sudden death in young people, as well as a cause of limiting heart failure symptoms at any age. Mutations in the cardiac sarcomere, the structural apparatus of the heart muscle, cause HCM and a diagnosis is made when maximal left ventricular (LV) wall thickness is ≥15 mm in the absence of another cause. Cardiovascular magnetic resonance (CMR) can reliably identify areas of increased LV wall thickness, as well as detailed characterization of myocardial structures such as the papillary muscles and mitral valve, with implications on management strategies. In addition, contrast-enhanced CMR with late gadolinium enhancement sequences (LGE) can identify areas of myocardial fibrosis/scarring in patients with HCM. Extensive LGE is an important marker for development of future systolic dysfunction and may identify patients at increased risk for ventricular tachyarrhythmias and cardiac mortality. As a result, CMR currently serves an important and evolving role in the evaluation of HCM patients by providing information with regard to diagnosis, morphology, and clinical course in HCM patients.

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