AJP Heart and Circulatory Physiology (Am J Physiol Heart Circ Physiol)

Publisher: American Physiological Society (1887- ), American Physiological Society

Journal description

The American Journal of Physiology: Heart and Circulatory Physiology publishes original investigations on the physiology of the heart, blood vessels, and lymphatics, including experimental and theoretical studies of cardiovascular function at all levels of organization ranging from the intact animal to the cellular, subcellular, and molecular levels. It embraces new descriptions of these functions and of their control systems, as well as their bases in biochemistry, biophysics, genetics, and cell biology. Preference is given to research that provides significant new insights into the mechanisms that determine the performance of the normal and abnormal heart and circulation.

Current impact factor: 4.01

Impact Factor Rankings

2015 Impact Factor Available summer 2015
2013 / 2014 Impact Factor 4.012
2012 Impact Factor 3.629
2011 Impact Factor 3.708
2010 Impact Factor 3.88
2009 Impact Factor 3.712
2008 Impact Factor 3.643
2007 Impact Factor 3.973
2006 Impact Factor 3.724
2005 Impact Factor 3.56
2004 Impact Factor 3.539
2003 Impact Factor 3.658
2002 Impact Factor 3.369
2001 Impact Factor 3.232
2000 Impact Factor 3.243
1999 Impact Factor 2.747

Impact factor over time

Impact factor

Additional details

5-year impact 3.86
Cited half-life 8.10
Immediacy index 0.72
Eigenfactor 0.06
Article influence 1.21
Website American Journal of Physiology - Heart and Circulatory Physiology website
Other titles American journal of physiology., Heart and circulatory physiology, Heart and circulatory physiology, AJP: Heart and circulatory physiology, AJP:heart, AJP:heart online
ISSN 1522-1539
OCLC 40069627
Material type Document, Periodical, Internet resource
Document type Internet Resource, Computer File, Journal / Magazine / Newspaper

Publisher details

American Physiological Society

  • Pre-print
    • Author can archive a pre-print version
  • Post-print
    • Author cannot archive a post-print version
  • Conditions
    • Author's Pre-print on pre-print servers
    • NIH, Wellcome Trust, HHMI, MRC and BBSRC authors will on their behalf have the Publisher's version/PDF deposited in PubMed Central for release 12 months after publication
    • Publisher's version/PDF cannot be used
    • May link to publisher version with DOI
    • Publisher last reviewed on 03/06/2015
  • Classification
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Publications in this journal

  • [Show abstract] [Hide abstract]
    ABSTRACT: We tested the hypothesis that vascular macrophage infiltration and O2 (-) release impairs sympathetic nerve α2 adrenergic autoreceptor (α2AR) function in mesenteric arteries (MA) of DOCA-salt hypertensive rats. Male rats were uninephrectomized (or sham operated). DOCA pellets were implanted s.c. in uninephrectomized rats who were provided high salt drinking water or high salt water with apocynin. Sham rats received tap water. Blood pressure was measured using radiotelemetry. Treatment of sham and DOCA-salt rats with liposome-encapsulated clodronate (Lipo-Clod) was used to deplete macrophages. After days 3-5, 10-13 and 18-21 of DOCA-salt treatment, MA and peritoneal fluid were harvested from euthanized rats. Norepinephrine (NE) release from periarterial sympathetic nerves was measured in vitro using amperometry with microelectrodes. Macrophage infiltration into MA, TNF-α and p22(phox) was measured using immunohistochemistry. Peritoneal macrophage activation was measured by flow cytometry. O2 (-) was measured using dihydroethidium staining. Hypertension developed over 28 days and apocynin reduced blood pressure at days 18-21. O2 (-) and macrophage infiltration were greater in DOCA-salt compared to sham MA after day 10. Peritoneal macrophage activation occurred after day 10 in DOCA-salt rats. Macrophages expressing TNF-α and p22(phox) were localized near sympathetic nerves. Impaired α2AR function and increased NE release from sympathetic nerves occurred in MA from DOCA-salt rats after day 18. Macrophage depletion reduced blood pressure and vascular O2 (-) while restoring α2AR function in DOCA-salt rats. Macrophage infiltration into the vascular adventitia contributes to increased blood pressure in DOCA-salt rats by releasing O2 (-), which disrupts α2AR function causing enhanced norepinephrine release from sympathetic nerves. Copyright © 2015, American Journal of Physiology - Heart and Circulatory Physiology.
    AJP Heart and Circulatory Physiology 08/2015; DOI:10.1152/ajpheart.00283.2015
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    ABSTRACT: Serum uric acid is a predictor of cardiovascular mortality in heart failure with reduced ejection fraction. However, the impact of uric acid on heart failure with preserved ejection fraction (HFpEF) remains unclear. Here, we investigated the association between hyperuricemia and mortality in HFpEF patients. Consecutive 424 patients, who were admitted to our hospital for decompensated heart failure and diagnosed as having HFpEF, were divided into two groups based on presence of hyperuricemia (serum uric acid ≥ 7 mg/dl or taking antihyperuricemic agents). We compared patient characteristics, echocardiographic data, cardio-ankle vascular index, and cardio-pulmonary exercise test findings between the two groups, and prospectively followed cardiac and all-cause mortality. Compared with the non-hyperuricemia group (n=170), the hyperuricemia group (n=254) had a higher prevalence of hypertension (P=0.013), diabetes mellitus (P=0.01), dyslipidemia (P=0.038), atrial fibrillation (P=0.001), and use of diuretics (P<0.001). Cardio-ankle vascular index (8.7 vs. 7.5, P<0.001), and VE/VCO2 slope (34.9 vs. 31.9, P=0.02) were also higher. In addition, peak VO2 (14.9 vs. 17.9 ml/kg/min, P<0.001) were lower. In the follow-up period (mean 897 days), cardiac and all-cause mortalities were significantly higher in those with hyperuricemia (P=0.006 and P=0.004, respectively). In the multivariable Cox proportional hazard analyses after adjusting for several confounding factors including chronic kidney disease and use of diuretics, hyperuricemia was an independent predictor of all-cause mortality (hazard ratio 1.98, 95% CI 1.036-3.793, P=0.039). Hyperuricemia is associated with arterial stiffness, impaired exercise capacity, and high mortality in HFpEF. Copyright © 2015, American Journal of Physiology - Heart and Circulatory Physiology.
    AJP Heart and Circulatory Physiology 08/2015; DOI:10.1152/ajpheart.00533.2015
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    ABSTRACT: Comment on : Differential effects of octanoate and heptanoate on myocardial metabolism during extracorporeal membrane oxygenation in an infant swine model. Copyright © 2015, American Journal of Physiology - Heart and Circulatory Physiology.
    AJP Heart and Circulatory Physiology 08/2015; DOI:10.1152/ajpheart.00620.2015
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    ABSTRACT: Vascular endothelial cells (ECs) respond to the hemodynamic forces stretch and shear stress by altering their morphology, functions, and gene expression. However, how they sense and differentiate between these two forces has remained unknown. Here we report that the plasma membrane itself differentiates between stretch and shear stress by undergoing transitions in its lipid phases. Uniaxial stretching and hypotonic swelling increased the lipid order of human pulmonary artery EC plasma membranes, thereby causing a transition from the liquid-disordered phase to the liquid-ordered phase in some areas, along with a decrease in membrane fluidity. In contrast, shear stress decreased the membrane lipid order and increased membrane fluidity. A similar increase in lipid order occurred when the artificial lipid bilayer membranes of giant unilamellar vesicles were stretched by hypotonic swelling, indicating that this is a physical phenomenon. The cholesterol content of EC plasma membranes significantly increased in response to stretch but clearly decreased in response to shear stress. Blocking these changes in the membrane lipid order by depleting membrane cholesterol with methyl-β-cyclodextrin or by adding cholesterol resulted in a marked inhibition of the EC response specific to stretch and shear stress, i.e., phosphorylation of PDGF receptors and phosphorylation of VEGF receptors, respectively. These findings indicate that EC plasma membranes differently respond to stretch and shear stress by changing their lipid order, fluidity and cholesterol content in opposite directions and that these changes in membrane physical properties are involved in the mechanotransduction that activates membrane receptors specific to each force. Copyright © 2015, American Journal of Physiology - Heart and Circulatory Physiology.
    AJP Heart and Circulatory Physiology 08/2015; DOI:10.1152/ajpheart.00241.2015
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    ABSTRACT: Left ventricular hypertrophy is associated with an increased risk of ventricular arrhythmias. However, the underlying molecular basis is poorly understood. It has been reported that small-conductance Ca(2+)-activated K(+) (SK) channels are involved in the pathogenesis of ventricular arrhythmias in heart failure. This study aimed to test the hypothesis that SK channel activity is increased via the Ca(2+)/calmodulin-dependent protein kinase II (CaMKII)-dependent pathway in hypertensive cardiac hypertrophy. Normotensive Wistar-Kyoto rats (WKYs) and spontaneous hypertensive rats (SHRs) were used. Whole cell membrane currents were recorded in isolated ventricular myocytes by the patch-clamp method, and the apamin-sensitive K(+) current (IKAS), inhibited by apamin (100 nM), an SK channel blocker, was evaluated. The IKAS at 40 mV was present in SHRs, whereas it was hardly detectable in WKYs (0.579±0.046 pA/pF vs. 0.022±0.062 pA/pF, both n=6, p<0.05). IKAS was almost completely abolished by 1 μM of KN-93, a CaMKII inhibitor, in SHRs. Optical recordings of the left ventricular anterior wall action potentials revealed that apamin prolonged the late phase of repolarization only in SHRs. A Western blot analysis of the SK channel protein isoforms demonstrated that SK2 was significantly increased in SHRs compared to WKYs (SK2/GAPDH 0.66±0.07 vs. 0.40±0.02, both n=6, p<0.05), whereas SK1 and SK3 did not differ between the groups. In addition, autophosphorylated CaMKII was significantly increased in SHRs (pCaMKII/GAPDH 0.80±0.06 vs. 0.58±0.06, both n=6, p<0.05) despite a comparable total amount of CaMKII between the groups. In conclusion, SK channels are upregulated via the enhanced activation of CaMKII in cardiac hypertrophy in SHRs. Copyright © 2014, American Journal of Physiology - Heart and Circulatory Physiology.
    AJP Heart and Circulatory Physiology 08/2015; DOI:10.1152/ajpheart.00825.2014
  • Wen-Juan Liu · Jian-Xin Deng · Gang Wang · Kai-Ping Gao · Ze-Xun Lin · Shuai-Ye Liu · Yong-Hui Wang · Jie Liu
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    ABSTRACT: Background In heterologous expression systems, KCNE2 has been demonstrated to interact with multiple α-subunits of voltage-dependent cation channels and modulate their functions. However, the physiological and pathological roles of KCNE2 in cardiomyocytes are poorly understood. Objective This study aims to investigate the effects of bidirectional modulation of KCNE2 expression on action potential duration (APD) and voltage-dependent K(+) channels in cardiomyocytes. Methods Adenoviral gene delivery and RNA interference were used to either increase or decrease KCNE2 expression in cultured neonatal and adult rat or neonatal mouse ventricular myocytes. Results Knockdown of KCNE2 prolonged APD in both neonatal and adult myocytes, whereas overexpression of KCNE2 shortened APD in neonatal but not adult myocytes. Consistent with the alterations in APD, KCNE2 knockdown decreased transient outward current (Ito) densities in neonatal and adult myocytes, whereas KCNE2 overexpression increased Ito densities in neonatal but not adult myocytes. Furthermore, KCNE2 knockdown accelerated the rates of Ito activation and inactivation, whereas KCNE2 overexpression slowed Ito gating kinetics in neonatal but not adult myocytes. The IK densities were remarkably affected by manipulation of KCNE2 expression in mouse but not rat cardiomyocytes. Simulating AP of rat ventricular myocyte with a mathematical model shows that the alterations in Ito current densities and gating properties can result in similar APD alterations in KCNE2 overexpression and knockdown cells. Conclusions Endogenous KCNE2 in cardiomyocytes is important in maintaining cardiac electrical stability mainly by regulating Ito and APD. Perturbation of KCNE2 expression may predispose the hearts to ventricular arrhythmia by prolonging APD. Copyright © 2014, American Journal of Physiology - Heart and Circulatory Physiology.
    AJP Heart and Circulatory Physiology 08/2015; DOI:10.1152/ajpheart.00757.2014
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    ABSTRACT: This study was undertaken to establish the role of NAD(P)H oxidase (Nox) in impaired vascular compensation to arterial occlusion that occurs in the presence of risk factors. Diet-induced obese mice (DIO) characterized by multiple comorbidities were utilized as a preclinical model of a population at significant risk for arterial occlusive disease. After distal femoral artery ligation, arterial pressure distal to the occlusion was decreased from ~80 to ~30 mmHg in both lean and DIO mice, indicating proximal collateral arteries to be the primary site of resistance that limited calf perfusion. Two weeks after ligation, significant vascular compensation occurred in lean but not DIO mice as evidenced by increased perfusion (147±48 vs. 49±29%) and collateral diameter (151±30 vs. 44±17%). Iliac-femoral artery expression of p22(phox), Nox2, Nox4, and p47(phox) were all increased with obesity (56-95%). Treatment of DIO mice with either apocynin or Nox2ds-tat, or whole-body ablation of either Nox2 or p47(phox) subunits in DIO mice, ameliorated the obesity-induced impairment in both collateral growth and hindlimb perfusion. The effect was greatest in the DIO mice with p47(phox) ablation. The results establish collateral resistance as the major limitation to calf perfusion in this preclinical model, implicate Nox2-p47(phox) interaction in the obesity-induced impairment of vascular compensation to arterial occlusion, and suggest selective Nox component suppression/inhibition may be effective as either primary or adjuvant therapy for claudicants. Copyright © 2015, American Journal of Physiology - Heart and Circulatory Physiology.
    AJP Heart and Circulatory Physiology 08/2015; DOI:10.1152/ajpheart.00180.2015
  • AJP Heart and Circulatory Physiology 08/2015; 309(4):H718. DOI:10.1152/ajpheart.00498.2015
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    ABSTRACT: The number and diameter of native collaterals in tissues of healthy mice vary widely, resulting in large differences in tissue injury in occlusive diseases. Recent studies suggest similar variation may exist in humans. Collateral variation in mice is determined by genetic background-dependent differences in embryonic collateral formation, by variation in maturation of the nascent collaterals, and by environmental factors such as aging that cause collateral rarefaction in the adult. Recently, formation of the collateral circulation in the brain was found to involve a unique VEGF-A-dependent "arteriolar" angiogenic sprouting-like mechanism. Elsewhere, chloride intracellular protein 4 (CLIC4) was implicated but not investigated directly, prompting the present study. Deletion of Clic4 had no effect on embryonic collaterogenesis. However, during collateral maturation from E18.5 to P7, reduced mural cell investment was observed and excessive pruning of collaterals occurred. Growth in collateral diameter was reduced. This resulted in 50% fewer collaterals of smaller diameter in the adult thus larger infarct volume after MCA occlusion. During collateral maturation, CLIC4 deficiency resulted in reduced expression of Vegfr2, Vegfr1, Vegfc and mural cell markers, but not notch-pathway genes. Overexpression of VEGF-A in Clic4(-/-) mice had no effect on collaterogenesis, but rescued the above defects in collateral maturation by preventing mural cell loss and collateral pruning, thus restoring collateral number and diameter and reducing stroke severity in the adult. CLIC4 is not required for collaterogenesis but is essential for perinatal maturation of nascent collaterals through a mechanism that supports VEGF signaling. Copyright © 2015, American Journal of Physiology - Heart and Circulatory Physiology.
    AJP Heart and Circulatory Physiology 08/2015; DOI:10.1152/ajpheart.00451.2015
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    ABSTRACT: The pathophysiological mechanisms of the immune activation of the smooth muscle cells are not well understood. Increased expression of Axl, a receptor tyrosine kinase, was recently found in arteries from coronary bypass grafting patients. In this study we hypothesized that Axl-dependent immune activation of smooth muscle cells regulates vein graft remodeling. We observed a 2-fold decrease in intimal thickening after vascular and systemic depletion of Axl in vein grafts. Local depletion of Axl had the greatest effect on immune activation, while systemic deletion of Axl reduced intima due to increase in apoptosis in vein grafts. The primary smooth muscle cells isolated from Axl knockout mice had reduced pro-inflammatory responses by preventing the STAT1 pathway. The absence of Axl increased SOCS1 expression in smooth muscle cells - a major inhibitory protein for STAT1. Ultrasound imaging suggested that vascular depletion of Axl reduced vein graft stiffness. Axl expression determined STAT1/SOCS1 balance in vein graft intima and progress of the remodeling. The result of this investigation demonstrates that Axl promotes the STAT1 signaling via inhibition of the SOCS1 in activated smooth muscle cells in vein graft remodeling. Copyright © 2015, American Journal of Physiology - Heart and Circulatory Physiology.
    AJP Heart and Circulatory Physiology 08/2015; DOI:10.1152/ajpheart.00495.2015
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    ABSTRACT: To determine whether chronic vagus nerve stimulation (VNS) mitigates myocardial infarction (MI)-induced remodeling of the intrinsic cardiac nervous system along with the cardiac tissue it regulates. Guinea pigs underwent VNS implantation on the right cervical vagus. Two weeks later, MI was produced by ligating the ventral descending coronary artery. VNS stimulation started 7 days post-MI (20 Hz, 0.9±0.2 mA, 14 sec ON, 48 sec OFF) (VNS-MI, n=7) and was compared to time matched MI animals with sham VNS (MI, n=7) versus untreated controls (n=8). Echocardiograms were performed before and at 90 days post-MI. At termination, intrinsic cardiac (IC) neuronal intracellular voltage recordings were obtained from whole mount neuronal plexuses. MI increased Left Ventricular End Systolic volume (LVESV) 30% (p=0.027) and reduced LV ejection fraction (LVEF) 6.5% (p<0.001) at 90 days post MI, compared to baseline. In the VNS-MI group, LVESV and LVEF did not differ from baseline. IC neurons showed depolarization of resting membrane potentials and increased input resistance in MI compared to MI-VNS and sham controls (p<0.05). Neuronal excitability and sensitivity to norepinephrine increased in MI and VNS-MI groups compared to controls (p<0.05). Synaptic efficacy, as determined by evoked responses to stimulating input axons, was reduced in VNS-MI compared to MI or controls (p<0.05). VNS induced changes in myocytes consistent with enhanced glycogenolysis and blunted the MI-induced increase in the pro-apoptotic BAX protein (p<0.05). VNS mitigates MI-induced remodeling of the intrinsic cardiac nervous system, correspondingly preserving ventricular function via both neural and cardiomyocyte dependent actions. Copyright © 2015, American Journal of Physiology - Heart and Circulatory Physiology.
    AJP Heart and Circulatory Physiology 08/2015; DOI:10.1152/ajpheart.00393.2015
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    ABSTRACT: Mitochondrial respiration has never been directly examined in intact cerebral arteries. We tested the hypothesis that mitochondrial energetics of large cerebral arteries ex vivo are sex-dependent. Approach and results: The Seahorse XFe24 analyzer was used to examine mitochondrial respiration in isolated cerebral arteries from adult male and female Sprague Dawley rats. We examined the role of nitric oxide (NO) on mitochondrial respiration under basal conditions, using L-NAME, and following pharmacological challenge using diazoxide (DZ), and also determined levels of mitochondrial and non-mitochondrial proteins using western blot, and vascular diameter responses to DZ. The components of mitochondrial respiration including basal respiration, ATP production, proton leak, maximal respiration, and spare respiratory capacity were elevated in females compared with males, but increased in both male and female arteries in the presence of the NOS inhibitor. Although acute DZ treatment had little effect on mitochondrial respiration of male arteries, it decreased the respiration in female arteries. Levels of mitochondrial proteins in Complexes I - V and the voltage-dependent anion channel protein were elevated in female compared with male cerebral arteries. The DZ induced vasodilation was greater in females than in males. Our findings show that substantial sex-differences in mitochondrial respiratory dynamics exist in large cerebral arteries and may provide the mechanistic basis for observations that the female cerebral vasculature is more adaptable after injury. Copyright © 2015, American Journal of Physiology - Heart and Circulatory Physiology.
    AJP Heart and Circulatory Physiology 08/2015; DOI:10.1152/ajpheart.00231.2015
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    ABSTRACT: Critically ill children can develop bleeding complications when treated with heparin-like drugs. These events are usually attributed to the anti-coagulant activity of these drugs. However, previous studies showed that Fibroblast Growth Factor-2 (FGF-2), a heparin binding growth factor released in the circulation of these patients, could precipitate intestinal hemorrhages in mice treated with the heparin-like drug pentosan polysulfate (PPS). Yet very little is known about how FGF-2 induces bleeding complications in combination with heparin-like drugs. Here, we examined the mechanisms by which circulating FGF-2 induces intestinal hemorrhages in mice treated with PPS. We used a well-characterized mouse model of intestinal hemorrhages induced by FGF-2 plus PPS. Adult FVB/N mice were infected with adenovirus carrying Lac-Z or a secreted form of recombinant human FGF-2, and injected with PPS, at doses that do not induce bleeding complications per se. Mice treated with FGF-2 in combination with PPS, developed an intestinal inflammatory reaction that increased the permeability and disrupted the integrity of submucosal intestinal vessels. These changes, together with the anticoagulant activity of PPS, induced lethal hemorrhages. Moreover, a genetically modified form of the endothelial-ligand Angiopoietin-1 (Ang-1*), which has powerful anti-permeability and anti-inflammatory activity, prevented the lethal bleeding complications without correcting the anti-coagulant status of these mice. These findings define new mechanisms through which FGF-2 and Ang-1* modulate the outcome of intestinal bleeding complications induced by PPS in mice, and may have wider clinical implications for critically ill children treated with heparin-like drugs. Copyright © 2015, American Journal of Physiology - Heart and Circulatory Physiology.
    AJP Heart and Circulatory Physiology 08/2015; DOI:10.1152/ajpheart.00373.2015
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    ABSTRACT: Dysfunctional vascular growth is a major contributor to cardiovascular disease, the leading cause of morbidity and mortality worldwide. Growth factor-induced activation of vascular smooth muscle cells (VSMCs) results in a phenotypic switch from a quiescent, contractile state to a proliferative state foundational to vessel pathology. Transforming growth factor-beta (TGFβ) is a multifunctional signaling protein capable of growth stimulation via Smad signaling. Although Smad signaling is well characterized in many tissues, its role in VSM growth disorders remains controversial. Recent data from our lab and others implicate the metabolic regulator AMP-activated protein kinase (AMPK) in VSM growth inhibition. We hypothesized that AMPK inhibits VSMC proliferation by reducing TGFβ-mediated growth in Smad-dependent fashion. Treatment of rat VSMCs with the AMPK agonist AICAR significantly decreased TGFβ-mediated activation of synthetic Smad2 and Smad3 and increased inhibitory Smad7. Flow cytometry and automated cell counting revealed that AICAR reversed TGFβ-mediated cell cycle progression at 24 hours and elevated cell numbers at 48 hours. TGFβ/Smad signaling increased the G0/G1 inducers cyclin D1/CDK4 and cyclin E/CDK2; however, AICAR reversed these events while increasing cytostatic p21. The specific role of Smad3 in AMPK-mediated reversal of TGFβ-induced growth was then explored using adenovirus-mediated Smad3 overexpression (Ad-Smad3). Ad-Smad3 cells increased cell cycle progression and cell numbers compared to Ad-GFP control cells, and these were restored to basal levels with concomitant AICAR treatment. These findings support a novel AMPK target in TGFβ/Smad3 for VSMC growth control and support continued investigation of AMPK as a possible therapeutic target for reducing vascular growth disorders. Copyright © 2014, American Journal of Physiology - Heart and Circulatory Physiology.
    AJP Heart and Circulatory Physiology 08/2015; DOI:10.1152/ajpheart.00846.2014
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    ABSTRACT: Beat-to-beat variability of the QT interval (QTV) is sought to provide an indirect non-invasive measure of sympathetic nerve activity, but a formal quantification of this relationship has not been provided. In this study we used power contribution analysis to study the relationship between QTV and muscle sympathetic nerve activity (MSNA). Here, ECG and MSNA were recorded in 10 healthy subjects in the supine position, followed by a 40° degree head-up tilt. Power spectrum analysis was performed using a linear autoregressive model with two external inputs; heart period variability (RRV) and MSNA. Total and low frequency power of QTV was decomposed into contributions by RRV, MSNA, and sources independent of RRV and MSNA. Results show that the percentage of MSNA power contribution to QT is very small, and does not change with tilt. RRV power contribution to QT power is notable and decreases with tilt, while the greatest percentage of QTV is independent of RRV and MSNA in both the supine position and after 40° head-up tilt. In conclusion, beat-to-beat QTV in normal subjects does not appear to be significantly affected by the rhythmic modulations observed in MSNA following low-medium degrees of orthostatic stimulation. Therefore MSNA oscillations may not represent a useful surrogate for cardiac sympathetic nerve at moderate levels of activity or, alternatively, sympathetic influences on QTV are complex and not quantifiable with linear shift-invariant autoregressive models. Copyright © 2015, American Journal of Physiology - Heart and Circulatory Physiology.
    AJP Heart and Circulatory Physiology 08/2015; DOI:10.1152/ajpheart.00230.2015
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    ABSTRACT: Mitochondrial respiration through electron transport chain (ETC) activity generates ATP and reactive oxygen species in eukaryotic cells. The modulation of mitochondrial respiration in vivo or under physiological conditions remains elusive largely due to the lack of appropriate approach to monitor ETC activity in a real time manner. Here, we show that ETC-coupled mitochondrial flash is a novel biomarker for monitoring mitochondrial respiration under pathophysiological conditions in cultured adult cardiac myocyte and perfused beating heart. Through real-time confocal imaging, we follow the frequency of a transient bursting fluorescent signal, named mitochondrial flash, from individual mitochondria within intact cells expressing a mitochondrial matrix-targeted probe, mt-cpYFP. This mt-cpYFP recorded mitochondrial flash has been shown to be composed of a major superoxide signal with a minor alkalization signal within the mitochondrial matrix. Through manipulating physiological substrates for mitochondrial respiration, we find a close coupling between flash frequency and the ETC electron flow as measured by oxygen consumption rate in cardiac myocyte. Stimulating electron flow under physiological conditions increases flash frequency. On the other hand, partially block or slowdown electron flow by inhibiting the FoF1 ATPase, which represents a pathological condition, transiently increases then decreases flash frequency. Limiting electron entrance at Complex I by knocking out Ndufs4, an assembling subunit of Complex I, suppresses mitochondrial flash activity. These results suggest that mitochondrial electron flow can be monitored by real-time imaging of mitochondrial flash. The mitochondrial flash frequency could be used as a novel biomarker for mitochondrial respiration under physiological and pathological conditions. Copyright © 2015, American Journal of Physiology - Heart and Circulatory Physiology.
    AJP Heart and Circulatory Physiology 08/2015; DOI:10.1152/ajpheart.00462.2015
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    ABSTRACT: Assisted reproductive technologies (ART) induce vascular dysfunction in humans and mice. In mice, ART-induced vascular dysfunction is related to epigenetic alteration of the eNOS gene resulting in decreased vascular eNOS expression and NOx synthesis. Melatonin is involved in epigenetic regulation and its administration to sterile women improves the success rate of ART. We hypothesized that addition of melatonin to culture media may prevent ART-induced epigenetic and cardiovascular alterations in mice. We, therefore, assessed mesenteric-artery responses to acetylcholine and arterial blood pressure together with DNA methylation of the eNOS gene promoter in vascular tissue and nitric oxide plasma concentration in 12-week old ART mice generated with and without addition of melatonin to culture media and in control mice. As expected, acetylcholine-induced mesenteric-artery dilation was impaired (P=0.008 vs. control) and mean arterial blood pressure increased (109.5±3.8 vs. 104.0±4.7 mm Hg, P=0.002 ART vs. control) in ART compared with control mice. These alterations were associated with altered DNA methylation of the eNOS gene promoter (P<0.001 vs. control) and decreased plasma nitric oxide concentration (10.1±11.1 vs. 29.5±8.0 µM (P<0.001 ART vs. control). Addition of melatonin (10(-6) M) to culture media prevented eNOS dysmethylation (P=0.005, vs. ART+vehicle), normalized nitric oxide plasma concentration (23.1±14.6 µM, P=0.002, vs. ART+vehicle) and mesentery-artery responsiveness to acetylcholine (P<0.008 vs. ART+vehicle) and prevented arterial hypertension (104.6±3.4 mmHg, P<0.003 vs. ART+vehicle). These findings provide proof of principle that modification of culture media prevents ART-induced vascular dysfunction. We speculate that this approach will also allow preventing ART-induced premature atherosclerosis in humans. Copyright © 2014, American Journal of Physiology - Heart and Circulatory Physiology.
    AJP Heart and Circulatory Physiology 08/2015; DOI:10.1152/ajpheart.00621.2014
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    ABSTRACT: We previously reported that ACE2 compensatory activity is impaired by the disintegrin and metalloprotease 17 (ADAM17) and lack of ACE2 is associated with oxidative stress in neurogenic hypertension. To investigate the relationship between ADAM17 and oxidative stress, Neuro2A cells were treated with Ang-II (100 nM) 24 h after vehicle or α-lipoic acid (LA: 500 µM). ADAM17 expression was increased by Ang-II (120.5 ±9.1 vs. 100.2 ±0.8%, p<0.05) and decreased after LA (69.0 ±0.3 vs. 120.5 ±9.1%, p<0.05). In other set of experiments, LA reduced ADAM17 (92.9 ±5.3 vs. 100.0 ±11.2 %, p<0.05) following its overexpression. Moreover, ADAM17 activity was reduced by LA in ADAM17-overexpressing cells (109.5 ±19.8 vs. 158.0 ±20.0 FU/min/µg protein, p<0.05), in which ADAM17 overexpression increased oxidative stress (114.1 ±2.5 vs. 101.0 ±1.0%, p<0.05). Conversely, LA-treated cells attenuated ADAM17 overexpression-induced oxidative stress (76.0 ±9.1 vs. 114.1 ±2.5%, p<0.05). In DOCA-salt-hypertensive mice, a model in which ADAM17 expression and activity are increased, hypertension was blunted by pre-treatment with LA (119.0 ±2.4 vs. 131.4 ±2.2 mmHg, p<0.05). In addition, LA improved dysautonomia and baroreflex sensitivity. Furthermore, LA blunted the increase in NADPH oxidase subunits expression, as well as the increase in ADAM17 and decrease in ACE2 activity in the hypothalamus of DOCA-salt hypertensive mice. Taken together, these data suggest that LA might preserve ACE2 compensatory activity by breaking the feed-forward cycle between ADAM17 and oxidative stress, resulting in a reduction of neurogenic hypertension. Copyright © 2015, American Journal of Physiology - Heart and Circulatory Physiology.
    AJP Heart and Circulatory Physiology 08/2015; DOI:10.1152/ajpheart.00259.2015