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: 3.84

Impact Factor Rankings

2015 Impact Factor Available summer 2016
2014 Impact Factor 3.838
2013 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 3.88
Cited half-life 9.10
Immediacy index 0.77
Eigenfactor 0.04
Article influence 1.19
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
    ​ yellow

Publications in this journal

  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: The activation of the calpain system is involved in the repair process following myocardial infarction (MI). However, the impact of the inhibition of calpain by calpastatin, its natural inhibitor, on scar healing and left ventricular (LV) remodeling is elusive. Methods and results: Mice ubiquitously overexpressing calpastatin (TG) and wild-type (WT) controls were subjected to an anterior coronary artery ligation. Mortality at 6 weeks was higher in TG mice (24% in WT vs. 44% in TG, p<0.05) driven by a significantly higher incidence of cardiac rupture during the first week post-MI, despite comparable infarct size, LV dysfunction and dilatation. Calpain activation post MI was blunted in TG myocardium. In TG mice inflammatory cell infiltration and activation were reduced in the infarct border zone (BZ), particularly affecting M2 macrophages and CD4+ T cells, which are crucial for scar healing. To elucidate the role of calpastatin overexpression in macrophages, we stimulated peritoneal macrophages obtained from TG and WT mice in vitro with IL-4, yielding an abrogated M2 polarization in TG but not in WT cells. Lymphopenic Rag1(-/-) mice receiving TG splenocytes prior to MI demonstrated decreased T cell recruitment and M2 macrophage activation in the BZ day 5 after MI compared to those receiving WT splenocytes. Conclusions: Calpastatin overexpression prevented the activation of the calpain system after MI. It also impaired scar healing, promoted LV rupture, and increased mortality. Defective scar formation was associated with blunted CD4+ T cell and M2 macrophage recruitment.
    AJP Heart and Circulatory Physiology 10/2015; DOI:10.1152/ajpheart.00594.2015
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    ABSTRACT: Recent studies show that hypoxia can alter the expressions of miRNAs. Whether hypoxia or hemorrhage-induced vascular hypo-reactivity is related to miRNAs and the underling mechanisms are not clear. Using hemorrhaged rats, hypoxia treated superior mesenteric arteries(SMAs) and vascular smooth muscle cells (VSMCs), the regulatory effects of miR124/ miR141 on vascular reactivity, and the relationship to RhoA and Rac1, and the mutual regulation of miR124 and miR141 were observed. The contractile responses of SMAs and VSMCs showed increase at early stage and decrease at late stage after hypoxia and hemorrhage. Forty-five miRNAs appeared significant changes in SMA after hypoxia, miR124 and miR141 changed most. Over-expressed or the antisense of miR124 or miR141 altered the vascular reactivity and the protein expression of RhoA and Rac1 after hypoxia. MiR124 inhibited Rac1 by acting at Rac1 mRNA 3'UTR, while increased RhoA by inhibiting miR141. MiR141 inhibited RhoA by acting at RhoA mRNA 3'UTR, while increased the Rac1 by inhibiting miR124. Further study found that miR124 inhibited miR141 via transcription factor Egr1, while miR141 inhibited miR124 via transcription factor Nrf2. The results suggest that miR124/miR141 participates in the regulation of vascular reactivity after hypoxia and hemorrhage via regulating the protein expression of RhoA and Rac1. In this process, miR124 and miR141 have mutual regulation. These findings provided potential targets to restore vascular function in the treatment of hemorrhagic shock and some other critical illness.
    AJP Heart and Circulatory Physiology 10/2015; DOI:10.1152/ajpheart.00651.2014
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    ABSTRACT: Cardiac c-kit(+) progenitor cells are important for maintaining cardiac homeostasis and can potentially contribute to myocardial repair. However, cellular physiology of human cardiac c-kit(+) progenitor cells is not well understood. The present study investigates the functional store-operated Ca(2+) entry (SOCE) channels and the potential role in regulating cell cycling and migration using confocal microscopy, RT-PCR, Western blot, co-immunoprecipitation, cell proliferation and migration assays. We found that SOCE channels mediated Ca(2+) influx, and TRPC1, STIM1 and Orai1 were involved in formation of SOCE channels in human cardiac c-kit(+) progenitor cells. Silencing TRPC1, STIM1, or Orai1 with the corresponding siRNA significantly reduced the Ca(2+) signaling through SOCE channels, decreased cell proliferation and migration, and reduced expression of cyclin D1, cyclin E, and/or p-Akt. Our results demonstrate the novel information that Ca(2+) signaling through SOCE channels regulates cell cycling and migration via activating cyclin D1, cyclin E and/or p-Akt in human cardiac c-kit(+) cells.
    AJP Heart and Circulatory Physiology 10/2015; DOI:10.1152/ajpheart.00260.2015
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    ABSTRACT: We hypothesized that potentiating the bioavailability of endothelial epoxyeicosatrienoic acids (EETs) via deletion of the gene for soluble epoxide hydrolase (sEH), or downregulation of sEH expression, enhances flow/shear stress-induced dilator responses (FID) of arterioles. Using male (M) and female (F) wild type (WT) and sEH-knockout (KO) mice, isolated gracilis muscle arterioles were cannulated and pressurized at 80 mmHg. Basal tone and increases in diameter of arterioles as a function of perfusate flow (5, 10, 15, 20 and 25 µl/min) were recorded. The magnitude of FID was significantly smaller, and associated with a greater arteriolar tone in M-WT than F-WT mice, revealing a sex-difference in FID. This sex-difference was abolished by deletion of the sEH gene, as evidenced by an enhanced FID in M-KO mice to a level comparable to those observed in F-KO and F-WT mice. These three groups of mice coincidentally exhibited an increased endothelial sensitivity to shear stress (smaller WSS50) and were hypotensive. Endothelial EETs participated in the mediation of enhanced FID in M-KO, F-KO and F-WT mice, without effects on FID of M-WT mice. Protein expression of sEH was downregulated by approximately 4-fold in vessels of F-WT compared to M-WT mice, paralleled with greater vascular EET levels that were statistically comparable to those observed in both male and female sEH-KO mice. In conclusion, sex-different regulation of sHE accounts for sex differences in flow mediated dilation of microvessels in gonadally intact mice.
    AJP Heart and Circulatory Physiology 10/2015; DOI:10.1152/ajpheart.00568.2015
  • Luis E Okamoto · Satish R Raj · Alfredo Gamboa · Cyndya Adriana Shibao · Amy C Arnold · Emily M Garland · Bonnie K Black · Ginnie Farley · André Diedrich · Italo Biaggioni
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    ABSTRACT: Sympathetic activation is thought to contribute to the inflammatory process associated with obesity, which is characterized by elevated circulating C-reactive protein (hsCRP) and interleukin-6 (IL-6). To evaluate whether sympathetic activation is associated with inflammation in the absence of obesity, we studied patients with postural tachycardia syndrome (POTS), a condition characterized by increased sympathetic tone in otherwise healthy individuals. Compared to 23 lean controls, 43 lean female POTS had greater vascular sympathetic modulation (low-frequency blood pressure variability, LFSBP, 3.2±0.4 vs. 5.5±0.6 mmHg(2) respectively, P=0.006), lower cardiac parasympathetic modulation (high-frequency heart rate variability, 1414±398 vs. 369±66 ms(2), P=0.001), and increased serum IL-6 (2.33±0.49 vs. 4.15±0.54 pg/mL, P=0.011) but this was not associated with increases in hsCRP, which was low in both groups (0.69±0.15 vs. 0.82±0.16 mg/L, P=0.736). To explore the contribution of adiposity to inflammation, we then compared 13 obese female POTS patients and 17 obese female controls to matched lean counterparts (13 POTS and 11 controls). Compared to lean controls, obese controls had increased LFSBP (3.3±0.5 vs. 7.0±1.1 mmHg(2); P=0.016), IL-6 (2.15±0.58 vs. 3.92±0.43 pg/mL; P=0.030) and hsCRP (0.69±0.20 vs. 3.47±0.72 mg/L; P=0.001). Obese and lean POTS had similarly high IL-6 but only obese POTS had increased hsCRP (5.76±1.99 mg/L vs. 0.65±0.26; P<0.001). In conclusion, sympathetic activation in POTS is associated with increased IL-6 even in the absence of obesity. The coupling between IL-6 and CRP, however, requires increased adiposity, likely through release of IL-6 by visceral fat.
    AJP Heart and Circulatory Physiology 10/2015; DOI:10.1152/ajpheart.00409.2015
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    ABSTRACT: Impairment of the lymphatic system is apparent in multiple inflammatory pathologies connected to elevated endotoxins such as lipopolysaccharide (LPS). However the direct mechanisms by which LPS influence the lymphatic contractility are not well understood. We hypothesized that a dynamic modulation of innate immune cell populations in mesentery under inflammatory conditions perturb tissue cytokine/chemokine homeostasis and subsequently influence lymphatic function. We used rats that were intraperitoneally injected with LPS (10mg/kg) to determine the changes in the profiles of innate immune cells in the mesentery and in the stretch-mediated contractile responses of isolated lymphatic preparations. Results demonstrated a reduction in the phasic contractile activity of mesenteric lymphatic vessels from LPS-injected rats and a severe impairment of lymphatic pump function and flow. There was a significant reduction in the number of neutrophils and an increase in monocytes/macrophages present on the lymphatic vessels and in the clear mesentery of the LPS group. This monocytes/macrophage population established a robust M2 phenotype, with the majority showing high expression of CD163 and CD206. Several cytokines and chemo-attractants for neutrophils and macrophages were significantly changed in the mesentery of LPS-injected rats. Treatment of lymphatic muscle cells (LMCs) with LPS showed significant changes in the expression of adhesion molecules, VCAM1, ICAM1, CXCR2 and Galectin-9. LPS-TLR4 mediated regulation of pAKT, pERK pIκB and pMLC20 in LMCs promoted both contractile and inflammatory pathways. Thus our data provide the first evidence connecting the dynamic changes in innate immune cells on/near the lymphatics and complex cytokine milieu during inflammation with lymphatic dysfunction.
    AJP Heart and Circulatory Physiology 10/2015; DOI:10.1152/ajpheart.00467.2015
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    ABSTRACT: Epoxyeicosatrienoic acids (EETs) have beneficial effects on cardiovascular disease. Soluble epoxide hydrolase (sEH) metabolizes EETs to less active diols, thus diminishing biological activity. sEH inhibitors can suppress the progression of atherosclerotic lesions in animal models. However, the regulation of sEH in vascular smooth muscle cells (VSMCs) and role of sEH in patients with atherosclerosis have not been evaluated. We hypothesize that sEH in VSMC plays a pivotal role in atherosclerosis and injury-induced neointima formation. In this study, sEH expression in human autopsy atherosclerotic plaque was determined by immunohistochemistry. In cultured rat and human VSMCs, the phenotypic switching marker and sEH expression induced by platelet-derived growth factor-BB (PDGF-BB) were examined by western blot analysis. Carotid-artery balloon injury was performed after adenovirus-mediated overexpression of sEH or oral administration of a potent sEH inhibitor in Sprague-Dawley rats. sEH was highly expressed in VSMCs of the intima and media within human atherosclerotic plaque. In vitro, PDGF-BB upregulated the expression in VSMCs post-transcriptionally and promoted cell proliferation and migration, the latter effect could be largely attenuated by sEH inhibitor. Adenovirus-mediated overexpression of sEH could mimic the effect of PDGF-BB, induced VSMC proliferation and migration. In vivo, sEH inhibitor significantly decreased the injury-induced neointima formation in a rat carotid-artery injury model. These data establish the impact of sEH expression on atherosclerotic progression and vascular remodeling after injury, thus identifying a novel integrative role of sEH in VSMC phenotypic modulation and migration. Blocking sEH activity may be a potential therapeutic approach for ameliorating vascular occlusive disease.
    AJP Heart and Circulatory Physiology 10/2015; DOI:10.1152/ajpheart.00289.2015
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    ABSTRACT: Background: In this large multicenter trial, we aimed to assess the effect of aerobic exercise training in stable coronary artery disease (CAD) patients on cellular markers of endothelial integrity, and examine their relation with improvement of endothelial function. Methods: Two-hundred CAD patients (LVEF >40%, 90% male, mean age 58.4±9.1 years) were randomized on a 1:1 base to a supervised 12-week rehabilitation program of either aerobic interval training (AIT) or aerobic continuous training (ACT) on a bicycle. At baseline and after 12 weeks, numbers of circulating CD34+/KDR+/CD45dim endothelial progenitor cells (EPC), CD31+/CD3+/CXCR4+ angiogenic T-cells and CD31+/CD42b- endothelial microparticles (EMP) were analyzed by flow cytometry. Endothelial function was assessed by flow-mediated dilation (FMD) of the brachial artery. Results: After 12 weeks of AIT or ACT, numbers of circulating EPC, angiogenic T-cells and EMP were comparable to baseline levels. Whereas improvement in peak VO2 was correlated to improvement in FMD (pearson r = 0.17, p = 0.035), a direct correlation of baseline or post-training EPC, angiogenic T-cells and EMP levels with FMD was absent. Baseline EMP related inversely to the magnitude of the increases in peak VO2 (spearman rho = -0.245, p = 0.027) and FMD (spearman rho = -0.374, p = 0.001) following exercise training. Conclusions: Endothelial function improvement in response to exercise training in CAD patients did not relate to altered levels of EPC and angiogenic T-cells and/or a diminished shedding of EMP into the circulation. EMP flow cytometry may be predictive of the increase in aerobic capacity and endothelial function.
    AJP Heart and Circulatory Physiology 10/2015; DOI:10.1152/ajpheart.00341.2015
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    ABSTRACT: Impairment of moment-to-moment adjustment of cerebral blood flow (CBF) via neurovascular coupling is thought to play a critical role in the genesis of cognitive impairment associated with aging and pathological conditions associated with accelerated cerebromicrovascular aging (e.g. hypertension, obesity). Although previous studies demonstrate that endothelial dysfunction plays a critical role in neurovascular uncoupling in these conditions, the role of endothelial NO mediation in neurovascular coupling responses is not well understood. To establish the link between endothelial function and functional hyperemia, neurovascular coupling responses were studied in mutant mice overexpressing or deficient in eNOS and the role of P2Y1 receptors in purinergic glioendothelial coupling was assessed. We found that genetic depletion of eNOS (eNOS(-/-)) and pharmacological inhibition of NO synthesis significantly decreased the CBF responses in the somatosensory cortex evoked by whisker stimulation and by administration of ATP. Overexpression of eNOS enhanced NO mediation of functional hyperemia. In control mice the selective and potent P2Y1 receptor antagonist MRS2179 attenuated both whisker stimulation-induced and ATP-mediated CBF responses, whereas in eNOS(-/-) mice the inhibitory effects of MRS2179 were blunted. Collectively, our findings provide additional evidence for purinergic glio-endothelial coupling during neuronal activity, highlighting the role of ATP-mediated activation of eNOS via P2Y1 receptors in functional hyperemia.
    AJP Heart and Circulatory Physiology 10/2015; DOI:10.1152/ajpheart.00463.2015
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    ABSTRACT: Cross-bridge cycling rate is an important determinant of cardiac output and its alteration can potentially contribute to reduced output in heart failure patients. Additionally, animal studies suggest that this rate can be regulated by muscle length. The purpose of this study was to investigate cross-bridge cycling rate and its regulation by muscle length under near-physiological conditions in intact right ventricular muscles of non-failing and failing human hearts. We acquired freshly explanted non-failing (n = 9) and failing (n = 10) human hearts. All experiments were performed on intact right ventricular cardiac trabeculae (n = 40) at physiological temperature and near the normal heart-rate range. The failing myocardium showed the typical heart-failure phenotype: a negative force-frequency relationship and β-adrenergic desensitization (P < 0.05), indicating the expected pathological myocardium in the right ventricles. We found that there exists a length-dependent regulation of cross-bridge cycling kinetics in human myocardium. Decreasing muscle length accelerated the rate of cross-bridge reattachment (ktr) in both non-failing and failing myocardium (P < 0.05) equally; there were no major differences between non-failing and failing myocardium at each respective length (P > 0.05), indicating this regulatory mechanism is preserved in heart failure. Length-dependent assessment of twitch kinetics mirrored these findings; normalized dF/dt slowed down with increasing length of the muscle, and was virtually identical in diseased tissue. This study shows for the first time that muscle length regulates cross-bridge kinetics in human myocardium under near-physiological conditions, and that those kinetics are preserved in right ventricular tissues of heart failure patients.
    AJP Heart and Circulatory Physiology 10/2015; DOI:10.1152/ajpheart.00685.2015
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    ABSTRACT: Hyperpolarized carbon-13 magnetic resonance spectroscopy ((13)C-MRS) enables the sensitive and non-invasive assessment of the metabolic changes occurring during myocardial ischemia-reperfusion. Ischemia-reperfusion models using hyperpolarized (13)C-MRS are established in heart preparations ex-vivo and in large animals in-vivo, but an in-vivo model in small animals would be advantageous to allow the study of reperfusion metabolism with neuroendocrine and inflammatory responses intact with the option to perform a greater number of experiments. A novel intact rat model of ischemia-reperfusion is presented which incorporates hyperpolarized (13)C-MRS to characterize reperfusion metabolism. Typically in an in-vivo model, a tissue input function (TIF) is required to account for apparent changes in the metabolism of injected hyperpolarized [1-(13)C]pyruvate resulting from changes in perfusion. While the measurement of a TIF by metabolic imaging is particularly challenging in small animals, the ratios of downstream metabolites can be used as an alternative. The ratio of [(13)C]bicarbonate-to-[1-(13)C]lactate (RatioBic/Lac) measured within 1-2min after coronary release decreased vs. baseline in ischemic rats (n=10, 15min occlusion, controls: n=10; p=0.017 for interaction, 2-way ANOVA). The decrease in oxidative pyruvate metabolism (RatioBic/Lac(Ischemia)/RatioBic/Lac(Baseline)) modestly correlated with area-at-risk (r=0.66; p=0.002). Hyperpolarized (13)C-MRS was also used to examine alanine production during ischemia, which is observed in ex-vivo models, but no significant change was noted, and metrics incorporating [1-(13)C]alanine did not substantially improve the discrimination of ischemic-reperfused myocardium from non-ischemic. This intact rat model, which mimics the human situation of reperfused myocardial infarction, could be highly valuable for the testing of new drugs to treat reperfusion injury and facilitating translational research.
    AJP Heart and Circulatory Physiology 10/2015; DOI:10.1152/ajpheart.00376.2015
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    ABSTRACT: Cerebral parenchymal arterioles (PA) regulate blood flow between pial arteries on the surface of the brain and the deeper microcirculation. Regulation of PA contractility differs from that of pial arteries and is not completely understood. Here, we investigated the hypothesis that the Ca2+ permeable vanilloid (V) transient receptor potential (TRP) channel TRPV3 can mediate endothelium-dependent dilation of cerebral PA. Using total internal reflection fluorescence microscopy (TIRFM) we found that carvacrol, a monoterpenoid compound derived from oregano, increased the frequency of unitary Ca2+ influx events through TRPV3 channels (TRPV3 sparklets) in endothelial cells from pial arteries and PAs. Carvacrol-induced TRPV3 sparklets were inhibited by the selective TRPV3 blocker isopentenyl pyrophosphate (IPP). TRPV3 sparklets have a greater unitary amplitude (∆F/F0 = 0.20) than previously characterized TRPV4 (∆F/F0 = 0.06) or TRPA1 (∆F/F0 = 0.13) sparklets, suggesting that TRPV3-mediated Ca2+ influx could have a robust influence on cerebrovascular tone. In pressure myography experiments, carvacrol caused dilation of cerebral PA that was blocked by IPP. Carvacrol-induced dilation was nearly abolished by removal of the endothelium and block of intermediate and small conductance Ca2+-activated K+ (IK and SK) channels. Together, these data suggest that TRPV3 sparklets cause dilation of cerebral parenchymal arterioles by activating IK and SK channels in the endothelium.
    AJP Heart and Circulatory Physiology 10/2015; DOI:10.1152/ajpheart.00140.2015
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    ABSTRACT: Perivascular adipose tissue (PVAT) reduces vasoconstriction to norepinephrine (NE). A potential mechanism by which PVAT could function to reduce vascular contraction is by decreasing the amount of NE to which the vessel is exposed. PVATs from male Sprague-Dawley rats were used to test the hypothesis that PVAT has a NE uptake mechanism. NE was detected by HPLC in mesenteric PVAT and isolated adipocytes. Uptake of NE (10 µM) was reduced by the norepinephrine transporter (NET) inhibitor nisoxetine (1 µM; 73.68±7.62%; all values reported as percent of vehicle), the 5-hydroxytryptamine transporter (SERT) inhibitor citalopram (100 nM) with the organic cation transporter 3 (OCT3) inhibitor corticosterone (100 µM; 56.18±5.21%), and the NET inhibitor desipramine (10 µM) with corticosterone (100 µM; 61.18±6.82%). Confocal imaging of PVAT stained with 4-[4-(dimethylamino)-styrl]-N-methylpyridium iodide (ASP(+)), a fluorescent substrate of cationic transporters, detected ASP(+) uptake into adipocytes. ASP(+) (2 µM) uptake was reduced by citalopram (100 nM; 66.68±6.43%), corticosterone (100 µM; 43.49±10.17%), nisoxetine (100 nM; 84.12±4.24%), citalopram with corticosterone (100 nM and 100 µM, respectively; 35.75±4.21%) and desipramine with corticosterone (10 µM and 100 µM, respectively, 50.47±5.78%). Expression of Slc22a3 (OCT3 gene) mRNA and protein in PVAT adipocytes was detected by RT-PCR and immunocytochemistry, respectively. These endpoints support the presence of a transporter-mediated NE uptake system within PVAT with a potential mediator being OCT3.
    AJP Heart and Circulatory Physiology 10/2015; DOI:10.1152/ajpheart.00308.2015
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    ABSTRACT: We investigated whether miR-145 has a cardioprotective effect in a rabbit model of myocardial infarction (MI) and in H9c2 rat cardiomyoblasts. Rabbits underwent 30 min of coronary occlusion followed by 2 days or 2 weeks of reperfusion. Control miRNA (control group; 2.5 nmol/kg, n=10) or miR-145 (miR-145 group, 2.5 nmol/kg, n=10) encapsulated in liposomes was intravenously administered immediately after the start of reperfusion. H9c2 rat cardiomyoblasts were transfected with miR-145. The MI size was significantly smaller in the miR-145 group than in the control group at 2 days and 2 weeks post-MI. MiR-145 had improved the cardiac function and remodeling at 2 weeks post-MI. These effects were reversed by chloroquine. Western blot analysis showed that miR-145 accelerated the transition of LC3B I to II and down-regulated p62/SQSTM1 at 2 days or 2 weeks after MI, but not at 4 weeks, and activated Akt in the ischemic area at 2 days after MI. MiR-145 inhibited the growth of H9c2 cells and accelerated the transition of LC3B I to II, and increased phosphorylated (p)Akt in the H9c2 cells at 2 days after miR-145 transfection. Antagomir-145 significantly abolished the morphological change, the transition of LC3B I to II, and the increased phosphorylated p-Akt induced by miR-145 in H9c2 cells. We determined fibroblast growth factor receptor substrate 2 (FRS2) mRNA to be a target of miR-145, both in an in vivo model and in H9c2 cells. In conclusion, post-MI treatment with miR-145 protected the heart through the induction of cardiomyocyte autophagy by targeting FRS2.
    AJP Heart and Circulatory Physiology 10/2015; DOI:10.1152/ajpheart.00709.2014
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    ABSTRACT: A growing number of extreme climate events are occurring in the setting of on-going climate change, with an increase in both the intensity and frequency. It has been shown that ambient temperature challenges have a direct and highly varied impact on cardiovascular health. With a rapidly growing number of publications on this subject, the objective was to review the recent literatures regarding the impact of cold and heat on human populations with regards to cardiovascular diseases (CVD) mortality/ morbidity while also examining lag effects, vulnerable subgroups and relevant mechanisms. Although the relative risk of morbidity/mortality associated with extreme temperature varied greatly across different studies, both cold and hot temperatures were associated with a positive mean excess of cardiovascular deaths or hospital admissions. Cause-specific study of CVD morbidity/mortality indicated that the sensitivity to temperature was disease-specific, with different patterns for acute and chronic ischemic heart disease. Vulnerability to temperature-related mortality was associated with sociodemographic characteristics including gender, age, location, socioeconomic status and comorbidities such as cardiac diseases, kidney diseases, diabetes and hypertension. Temperature-induced damage is thought to be related to enhanced sympathetic reactivity followed by activation of the sympathetic nervous system, rennin-angiotensin system, as well as dehydration and a systemic inflammatory response. Future research should focus on multidisciplinary adaptation strategies that incorporate epidemiology, climatology, indoor/building environments, energy usage, labor legislative perfection and human thermal comfort models. Studies on the underlying mechanism by which temperature challenge induces pathophysiological response and CVD await profound and lasting investigation.
    AJP Heart and Circulatory Physiology 10/2015; DOI:10.1152/ajpheart.00199.2015
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    ABSTRACT: The aim of the present study was to determine whether long-term high salt intake in the drinking water induced hypertension in WT mice and whether a chymase inhibitor or other antihypertensive drugs could reverse the increase of blood pressure. WT male mice (8wk) were supplied with 2%salt water for 12 weeks (high-salt group) or high-salt drinking water plus an oral chymase inhibitor (TPC-806) at 4 different doses (25, 50, 75, or 100 mg/kg), or captopril, losartan, HCTZ, eplerenone, or amlodipine. The control groups were given normal water with or without the chymase inhibitor. Blood pressure and heart rate gradually showed a significant increase in the high-salt group, while a dose-dependent depressor effect of the chymase inhibitor was observed. There was also partial improvement of hypertension in the losartan and eplerenone groups, but not in the rest of drug groups. A high salt load significantly increased chymase-dependent Ang II-forming activity in the alimentary tract and the relative contribution of chymase to Ang II formation showed a significant increase in skin and skeletal muscle, while ACE-dependent Ang II-forming activity and its relative contribution were reduced by high salt intake. Plasma and urinary RAS components were significantly increased in the high-salt group, but were significantly suppressed in the chymase inhibitor group. In conclusion, 2% salt water drinking for 12 weeks caused moderate hypertension and activated the RAS in WT mice. A chymase inhibitor suppressed both elevation of blood pressure and the heart rate, indicating definite involvement of chymase in the salt-sensitive hypertension.
    AJP Heart and Circulatory Physiology 10/2015; DOI:10.1152/ajpheart.00721.2014
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    ABSTRACT: Circulating angiogenic cells (CACs) are monocyte-derived cells with endothelial characteristics, which contribute to both angiogenesis and arteriogenesis in a paracrine way. Interferon-beta (IFN-ß) is known to inhibit these divergent processes in animals and patients. We hypothesized that IFN-ß might act by affecting the differentiation and function of CACs. CACs were cultured from peripheral blood mononuclear cells (MNCs) and phenotypically characterized by surface expression of monocytic and endothelial markers. IFN-β significantly reduced the number of CACs by 18-64%. Apoptosis was not induced by IFN-β, neither in MNCs during differentiation, nor after maturation to CACs. Rather, IFN-β impaired adhesion to- and spreading on fibronectin, which was dependent on α5β1 (VLA-5) integrin. IFN-β affected the function of VLA-5 in mature CACs, leading to rounding and detachment of cells, by induction of calpain 1 activity. Cell rounding and detachment was completely reversed by inhibition of calpain 1 activity in mature CACs. During in vitro capillary formation, CAC addition and calpain 1 inhibition enhanced sprouting of endothelial cells to a comparable extent, but were not sufficient to rescue tube formation in the presence of IFN-β. We show that the IFN-β-induced reduction of the numbers of in vitro differentiated CACs is based on activation of calpain 1, resulting in an attenuated adhesion to extracellular matrix proteins via VLA-5. In vivo this could lead to inhibition of vessel formation due to reduction of the locally recruited CAC numbers and their paracrine angiogenic factors.
    AJP Heart and Circulatory Physiology 10/2015; DOI:10.1152/ajpheart.00810.2014
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    ABSTRACT: S-glutathionylation of cardiac myosin-binding protein-C (cMyBP-C) induces Ca(2+)-sensitization and a slowing of cross-bridge kinetics as a result of increased oxidative signaling. Although there is evidence for a role of oxidative stress in disorders associated with hypertrophic cardiomyopathy (HCM), this mechanism is not well understood. We investigated whether oxidative myofilament modifications may be in part responsible for diastolic dysfunction in HCM. We administered N-acetylcysteine (NAC) for 30 days to one-month old wild-type mice and to transgenic mice expressing a mutant tropomyosin (Tm-E180G) and to non-transgenic littermates. Tm-E180G hearts demonstrate a phenotype similar to human HCM. After NAC-administration, the morphology and diastolic function of Tm-E180G mice was not significantly different from controls, indicating that NAC had reversed baseline diastolic dysfunction and hypertrophy in our model. NAC administration also increased sarco(endo)plasmic reticulum Ca(2+) ATPase protein expression, reduced extracellular signal-related kinase 1/2 phosphorylation, and normalized phosphorylation of phospholamban, as assessed by Western blot. Detergent-extracted fiber bundles from NAC-administered Tm-E180G mice showed near-non-transgenic (NTG) myofilament Ca(2+)-sensitivity. Additionally, we found NAC increased tension cost and rate of cross-bridge reattachment. Tm-E180G myofilaments were found to have a significant increase in S-glutathionylation of cMyBP-C, which was returned to NTG-levels upon NAC-administration. Taken together, our results indicate that oxidative myofilament modifications are an important mediator in diastolic function and by relieving this modification we were able to reverse established diastolic dysfunction and hypertrophy in HCM.
    AJP Heart and Circulatory Physiology 10/2015; DOI:10.1152/ajpheart.00339.2015