Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An enhancement of peripheral chemoreflex sensitivity contributes to sympathetic hyperactivity in chronic heart failure (CHF) rabbits. The enhanced chemoreflex function in CHF involves augmented carotid body (CB) chemoreceptor activity via upregulation of the angiotensin II (ANG II) type 1 (AT(1))-receptor pathway and downregulation of the neuronal nitric oxide synthase (nNOS)-nitric oxide (NO) pathway in the CB. Here we investigated whether exercise training (EXT) normalizes the enhanced peripheral chemoreflex function in CHF rabbits and possible mechanisms mediating this effect. EXT partially, but not fully, normalized the exaggerated baseline renal sympathetic nerve activity (RSNA) and the response of RSNA to hypoxia in CHF rabbits. EXT also decreased the baseline CB nerve single-fiber discharge (4.9 +/- 0.4 vs. 7.7 +/- 0.4 imp/s at Po(2) = 103 +/- 2.3 Torr) and the response to hypoxia (20.6 +/- 1.1 vs. 36.3 +/- 1.3 imp/s at Po(2) = 41 +/- 2.2 Torr) from CB chemoreceptors in CHF rabbits, which could be reversed by treatment of the CB with ANG II or a nNOS inhibitor. Our results also showed that NO concentration and protein expression of nNOS were increased in the CBs from EXT + CHF rabbits, compared with that in CHF rabbits. On the other hand, elevated ANG II concentration and AT(1)-receptor overexpression of the CBs in CHF state were blunted by EXT. These results indicate that EXT normalizes the CB chemoreflex in CHF by preventing an increase in afferent CB chemoreceptor activity. EXT reverses the alterations in the nNOS-NO and ANG II-AT(1)-receptor pathways in the CB responsible for chemoreceptor sensitization in CHF.
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PMID:Exercise training improves peripheral chemoreflex function in heart failure rabbits. 1863 72

Fatty acids (FAs) are acquired from free FA associated with albumin and lipoprotein triglyceride that is hydrolyzed by lipoprotein lipase (LpL). Hypertrophied hearts shift their substrate usage pattern to more glucose and less FA. However, FAs may still be an important source of energy in hypertrophied hearts. The aim of this study was to examine the importance of LpL-derived FAs in hypertensive hypertrophied hearts. We followed cardiac function and metabolic changes during 2 wk of angiotensin II (ANG II)-induced hypertension in control and heart-specific lipoprotein lipase knockout (hLpL0) mice. Glucose metabolism was increased in ANG II-treated control (control/ANG II) hearts, raising it to the same level as hLpL0 hearts. FA uptake-related genes, CD36 and FATP1, were reduced in control/ANG II hearts to levels found in hLpL0 hearts. ANG II did not alter these metabolic genes in hLpL0 mice. LpL activity was preserved, and mitochondrial FA oxidation-related genes were not altered in control/ANG II hearts. In control/ANG II hearts, triglyceride stores were consumed and reached the same levels as in hLpL0/ANG II hearts. Intracellular ATP content was reduced only in hLpL0/ANG II hearts. Both ANG II and deoxycorticosterone acetate-salt induced hypertension caused heart failure only in hLpL0 mice. Our data suggest that LpL activity is required for normal cardiac metabolic compensation to hypertensive stress.
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PMID:Cardiac metabolic compensation to hypertension requires lipoprotein lipase. 1864 80

We tested the hypothesis that heart rate (HR) reduction, induced by the selective hyperpolarization-activated current inhibitor ivabradine (Iva), might improve left ventricular (LV) function, structure, and electrical remodeling in severe post-myocardial infarction (MI) chronic heart failure (HF). MI was produced in adult male Wistar rats. After 2 mo, echocardiography was performed before the randomization into MI and MI + Iva (10 mg x kg(-1) x day(-1)) groups. After 3 mo of treatment, echocardiography and 24-h telemetry were recorded. Cardiac collagen, mRNA, and protein expressions of angiotensin-converting enzyme (ACE) and ANG II type 1 (AT(1)) receptor were quantified. As a result, at 2 mo post-MI, all rats displayed severe congestive HF signs (ejection fraction < 30%). At 5 mo post-MI, body and heart weights were similar in the MI and MI + Iva groups. LV ejection fraction and LV end-diastolic pressure were worsened in the MI group, whereas both were improved with Iva. Iva reduced HR by 10.4% (P < 0.03 vs. MI) and ventricular premature complexes by 89% (P < 0.03) and improved HR variability (standard deviation of the RR interval) by 22% (P < 0.05). There were no effects of Iva on PR, QRS, and QT durations. Interstitial fibrosis in the MI-remote LV was markedly reduced by Iva (4.0 +/- 0.1 vs. 1.8 +/- 0.1%, P < 0.005). Increases in ventricular gene and protein expressions of ACE and AT(1) receptor in MI were completely blunted by Iva. In conclusion, these data indicated that HR reduction by Iva prevents the worsening of LV dysfunction and remodeling that may be related to a downregulation of cardiac renin-angiotensin-aldosterone system transcripts. Such beneficial effects of Iva on cardiac remodeling open new clinical perspectives for the treatment of severe HF.
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PMID:Beneficial effects of delayed ivabradine treatment on cardiac anatomical and electrical remodeling in rat severe chronic heart failure. 1907 74

To better understand the pathophysiological role of angiotensin II (ANG II) in the dynamic autonomic regulation of heart rate (HR), we examined the effects of intravenous administration of ANG II (10 microg.kg(-1).h(-1)) on the transfer function from vagal or sympathetic nerve stimulation to HR in anesthetized rabbits with sinoaortic denervation and vagotomy. In the vagal stimulation group (n = 7), we stimulated the right vagal nerve for 10 min using binary white noise (0-10 Hz). The transfer function from vagal stimulation to HR approximated a first-order low-pass filter with pure delay. ANG II attenuated the dynamic gain from 7.6 +/- 0.9 to 5.8 +/- 0.9 beats.min(-1).Hz(-1) (means +/- SD; P < 0.01) without affecting the corner frequency or pure delay. In the sympathetic stimulation group (n = 7), we stimulated the right postganglionic cardiac sympathetic nerve for 20 min using binary white noise (0-5 Hz). The transfer function from sympathetic stimulation to HR approximated a second-order low-pass filter with pure delay. ANG II slightly attenuated the dynamic gain from 10.8 +/- 2.6 to 10.2 +/- 3.1 beats.min(-1).Hz(-1) (P = 0.049) without affecting the natural frequency, damping ratio, or pure delay. The disproportional suppression of the dynamic vagal and sympathetic regulation of HR would result in a relative sympathetic predominance in the presence of ANG II. The reduced high-frequency component of HR variability in patients with cardiovascular diseases, such as myocardial infarction and heart failure, may be explained in part by the peripheral effects of ANG II on the dynamic autonomic regulation of HR.
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PMID:Angiotensin II disproportionally attenuates dynamic vagal and sympathetic heart rate controls. 1925 92

ANG is a plasma protein with angiogenic and ribonucleolytic activity implicated in tumor growth, heart failure, wound healing, asthma, and the composition of the adult gut microflora. Human mast cells (HuMC) are similarly associated with modulation of vascular permeability, angiogenic processes, wound healing, and asthma. We hypothesized that HuMC express and secrete ANG in response to divergent stimuli. ANG expression was evaluated in the LAD2 HMC, the HMC-1, and CD34+-derived HuMC, following exposure to live Escherichia coli, TLR ligands, or neuropeptides and following FcepsilonRI aggregation. Expression and production of ANG were determined by microarray analysis, qRT-PCR, confocal microscopy, and ELISA. Microarray analysis showed that ANG is up-regulated by LAD2 cells exposed to live E. coli. qRT-PCR analysis revealed that LAD2, HMC-1, and HuMC constitutively expressed ANG mRNA and that it was up-regulated by exposure to E. coli. Activation of HuMC by FcepsilonRI aggregation resulted in release of small amounts of ANG (<100 pg/mL), whereas compound 48/80, NGF, LPS, PGN, and flagellin activated HuMC to secrete >160 pg/mL ANG. These observations demonstrate that HuMC store and secrete ANG to a variety of stimuli and suggest that MC-derived ANG is available in the subsequent inflammatory response.
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PMID:Human mast cells synthesize and release angiogenin, a member of the ribonuclease A (RNase A) superfamily. 1962 71

Angiotensin type 1 receptors (AT(1)Rs) play a critical role in a variety of physiological functions and pathophysiological states. They have been strongly implicated in the modulation of sympathetic outflow in the brain. An understanding of the mechanisms by which AT(1)Rs are regulated in a variety of disease states that are characterized by sympathoexcitation is pivotal in development of new strategies for the treatment of these disorders. This review concentrates on several aspects of AT(1)R regulation in the setting of chronic heart failure (CHF). There is now good evidence that AT(1)R expression in neurons is mediated by activation of the transcription factor activator protein 1 (AP-1). This transcription factor and its component proteins are upregulated in the rostral ventrolateral medulla of animals with CHF. Because the increase in AT(1)R expression and transcription factor activation can be blocked by the AT(1)R antagonist losartan, a positive feedback mechanism of AT(1)R expression in CHF is suggested. Oxidative stress has also been implicated in the regulation of receptor expression. Recent data suggest that the newly discovered catabolic enzyme angiotensin-converting enzyme 2 (ACE2) may play a role in the modulation of AT(1)R expression by altering the balance between the octapeptide ANG II and ANG- (1-7). Finally, exercise training reduces both central oxidative stress and AT(1)R expression in animals with CHF. These data strongly suggest that multiple central and peripheral influences dynamically alter AT(1)R expression in CHF.
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PMID:Regulation of central angiotensin type 1 receptors and sympathetic outflow in heart failure. 1971 36

Cardiac hypertrophy is not only an adaptational state before heart failure but also is an independent risk factor for ischemia, arrhythmia, and sudden death. However, the direct effects of hypercholesterolemia on the myocardium and mechanisms are not completely understood. It has been demonstrated that peroxisome proliferator-activated receptor-gamma (PPARgamma) ligand agonists attenuate cardiac hypertrophy through anti-inflammatory effects. The present study investigated the effects of PPARgamma agonists on hypercholesterolemia-dependent, renin-angiotensin-system-related cardiac hypertrophy. The findings showed that left ventricular hypertrophy, eminent cardiomyocyte hypertrophy, and lipid deposits in myocardium were observed in the rats fed a cholesterol-rich diet for 6 months, while these characteristic pathological alterations and the increase in angiotensin II (ANG II) level and over-expression of angiotensin II type 1 receptor (AT(1)R) in the left ventricular tissues induced by the cholesterol-rich diet were significantly suppressed to equal extents by rosiglitazone and irbesartan. In contrast, expression of angiotensin II type 2 receptor (AT(2)R) was upregulated by these two drugs. In addition, lipid metabolism was markedly improved. The above findings suggest that the cardioprotection of the PPARgamma agonist against cardiac hypertrophy evoked by hypercholesterolemia in rats is mediated partially by the improvement of lipid profile, the reduction of ANG II level in the local tissue along with the downregulation of AT(1)R expression, and upregulation of AT(2)R expression.
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PMID:The inhibitory effects of rosiglitazone on cardiac hypertrophy through modulating the renin-angiotensin system in diet-induced hypercholesterolemic rats. 2002 60

Elevated central angiotensin II (ANG II) plays a critical role in the sympathoexcitation of chronic heart failure (CHF) by stimulating upregulated ANG II type 1 receptors (AT(1)R) in the rostral ventrolateral medulla (RVLM). However, the link between enhanced ANG II signaling and alterations in the electrophysiological characteristics of neurons in the RVLM remains unclear. In the present experiments, we screened for potentially altered genes in the medulla of rats with CHF that are directly related to neuronal membrane conductance using the Rat Genome 230 2.0 Array GeneChip. We found that CHF rats exhibited a 2.1-fold reduction in Kv4.3 gene expression, one of the main voltage-gated K(+) channels, in the medulla. Real-time RT-PCR and Western blot analysis confirmed the downregulation of Kv4.3 in the RVLM of CHF rats. In intact animals, we found that microinjection of the voltage-gated potassium channel blocker, 4-aminopyridine, into the RVLM evoked a sympathoexcitation and hypertension in both normal and CHF rats. CHF rats exhibited smaller responses to 4-aminopyridine than did normal rats. Finally, we used a neuronal cell line (CATH.a neurons) to explore the effect of ANG II on Kv4.3 expression and function. We found that ANG II treatment significantly downregulated mRNA and protein expression of Kv4.3 and decreased the A-type K(+) current. Employing this cell line, we also found that the ANG II-induced inhibition of Kv4.3 mRNA expression was attenuated by the superoxide scavenger Tempol and the p38 MAPK inhibitor SB-203580. The effects of ANG II were abolished by the AT(1)R antagonist losartan. We conclude that the sympathoexcitation observed in the CHF state may be due, in part, to an ANG II-induced downregulation of Kv4.3 expression and subsequent decrease in K(+) current, thereby increasing the excitability of neurons in the RVLM. The ANG II-induced inhibition of Kv4.3 mRNA expression was mediated by ANG II-AT(1)R-ROS-p38 MAPK signaling.
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PMID:Downregulated Kv4.3 expression in the RVLM as a potential mechanism for sympathoexcitation in rats with chronic heart failure. 2004 44

Reactive oxygen species (ROS), particularly superoxide (O(2)(.-)), have been identified as key signaling intermediates in ANG II-induced neuronal activation and sympathoexcitation associated with cardiovascular diseases, such as hypertension and heart failure. Studies of the central nervous system have identified NADPH oxidase as a primary source of O(2)(.-) in ANG II-stimulated neurons; however, additional sources of O(2)(.-), including mitochondria, have been mostly overlooked. Here, we tested the hypothesis that ANG II increases mitochondria-produced O(2)(.-) in neurons and that increased scavenging of mitochondria-produced O(2)(.-) attenuates ANG II-dependent intraneuronal signaling. Stimulation of catecholaminergic (CATH.a) neurons with ANG II (100 nM) increased mitochondria-localized O(2)(.-) levels, as measured by MitoSOX Red fluorescence. This response was significantly attenuated in neurons overexpressing the mitochondria-targeted O(2)(.-)-scavenging enzyme Mn-SOD. To examine the biological significance of the ANG II-mediated increase in mitochondria-produced O(2)(.-), we used the whole cell configuration of the patch-clamp technique to record the well-characterized ANG II-induced inhibition of voltage-gated K(+) current (I(Kv)) in neurons. Adenovirus-mediated Mn-SOD overexpression or pretreatment with the cell-permeable antioxidant tempol (1 mM) significantly attenuated ANG II-induced inhibition of I(Kv). In contrast, pretreatment with extracellular SOD protein (400 U/ml) had no effect. Mn-SOD overexpression also inhibited ANG II-induced activation of Ca(2+)/calmodulin kinase II, a redox-sensitive protein known to modulate I(Kv). These data indicate that ANG II increases mitochondrial O(2)(.-), which mediates, at least in part, ANG II-induced activation of Ca(2+)/calmodulin kinase II and inhibition of I(Kv) in neurons.
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PMID:Mitochondria-produced superoxide mediates angiotensin II-induced inhibition of neuronal potassium current. 2008 30

Exercise training (EX) normalizes sympathetic outflow and plasma ANG II in chronic heart failure (CHF). The central mechanisms by which EX reduces this sympathoexcitatory state are unclear, but EX may alter components of the brain renin-angiotensin system (RAS). Angiotensin-converting enzyme (ACE) may mediate an increase in sympathetic nerve activity (SNA). ACE2 metabolizes ANG II to ANG-(1-7), which may have antagonistic effects to ANG II. Little is known concerning the regulation of ACE and ACE2 in the brain and the effect of EX on these enzymes, especially in the CHF state. This study aimed to investigate the effects of EX on the regulation of ACE and ACE2 in the brain in an animal model of CHF. We hypothesized that the ratio of ACE to ACE2 would increase in CHF and would be reduced by EX. Experiments were performed on New Zealand White rabbits divided into the following groups: sham, sham + EX, CHF, and CHF + EX (n = 5 rabbits/group). The cortex, cerebellum, medulla, hypothalamus, paraventricular nucleus (PVN), nucleus tractus solitarii (NTS), and rostral ventrolateral medulla (RVLM) were analyzed. ACE protein and mRNA expression in the cerebellum, medulla, hypothalamus, PVN, NTS, and RVLM were significantly upregulated in CHF rabbits (ratio of ACE to GAPDH: 0.3 +/- 0.03 to 0.8 +/- 0.10 in the RVLM, P < 0.05). EX normalized this upregulation compared with CHF (0.8 +/- 0.1 to 0.4 +/- 0.1 in the RVLM). ACE2 protein and mRNA expression decreased in CHF (ratio of ACE2 to GAPDH: 0.3 +/- 0.02 to 0.1 +/- 0.01 in the RVLM). EX increased ACE2 expression compared with CHF (0.1 +/- 0.01 to 0.8 +/- 0.1 in the RVLM). ACE2 was present in the cytoplasm of neurons and ACE in endothelial cells. These data suggest that the activation of the central RAS in animals with CHF involves an imbalance of ACE and ACE2 in regions of the brain that regulate autonomic function and that EX can reverse this imbalance.
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PMID:Exercise training normalizes ACE and ACE2 in the brain of rabbits with pacing-induced heart failure. 2009 67


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