neuropeptide-y and Cardiomegaly

Neuropeptide Y (NPY) has been well known to induce Cardiomyocyte Hypertrophy (CH), which is possibly caused by disruption of cardiac cell energy balance. As mitochondria is losely related to energy metabolism, in this study, we investigated the changes in mitochondrial Dynamics-related protein (Drp1) expression under the action of NPY. miRNA-29a, a endogenous noncoding small molecule RNA which is involved in many cardiac diseases, by using a bioinformatics tool, we found a potential binding site of miRNA-29a on the Drp1 mRNA, and suggesting that miRNA-29a might play a regulatory role.. To investigate the role of miR-29a-3p in the process of NPY-induced CH, and further explore it's predicted relationship with Drp1.. The expression levels of miR-29a-3p and Atrial Natriuretic Peptide (ANP) were performed by the method of fluorescence quantitative PCR, in addition, expression of Drp1 in treated and control groups were performed by western blot analysis.] Results: We found NPY leads to the CH and up-regulation of ANP expression levels. We also found significant up-regulation of Drp1 expression and down-regulation of miR-29a-3p expression in NPY-treated cells. The decrease in miR-29a-3p expression may lead the increase expression level of Drp1. We found that the expression of ANP increased after NPY treatment. When Drp1 protein was silenced, the high expression of ANP was inhibited.. In this study, we found up-regulation of Drp1 in cells treated with NPY. Drp1 mRNA is a predicted target for miR-29a-3p, and the expression of Drp1 was attenuated by miR-29a-3p. Therefore, NPY leads to down-regulation of miR-29a-3p expression, up-regulation of Drp1 expression, and NPY leads to CH. Correspondingly, miR-29a-3p can counteract the effects of NPY. This may be a new way, which could be used in diagnosis and treatment plan for CH.

Topics: Animals; Animals, Newborn; Cardiomegaly; Dynamins; Gene Expression Regulation; MicroRNAs; Myocytes, Cardiac; Neuropeptide Y; Rats; Rats, Sprague-Dawley

Cardiac remodelling and heart failure are promoted by persistent sympathetic activity. We recently reported that nuclear receptor Nur77 may protect against sympathetic agonist-induced cardiac remodelling in mice. The sympathetic co-transmitter neuropeptide Y (NPY) is co-released with catecholamines and is a known cardiac modulator and predictor of heart failure mortality. Recently, transcriptome analyses revealed NPY as a putative target of Nur77. In this study, we assess whether Nur77 modulates adverse cardiac remodelling via NPY signalling.. Nur77 represses NPY expression in the PC12 adrenal chromaffin cell line. Accordingly, NPY levels are higher in adrenal gland, plasma, and heart from Nur77-KO compared to wild-type mice. Conditioned medium from Nur77-silenced chromaffin cells and serum from Nur77-KO mice induce marked hypertrophy in cultured neonatal rat cardiomyocytes, which is inhibited by the NPY type 1 receptor (NPY1R) antagonist BIBO3304. In cardiomyocytes from Nur77-KO mice, intracellular Ca2+ is increased partially via the NPY1R. This is independent from elevated circulating NPY since cardiomyocyte-specific Nur77-deficient mice (CM-KO) do not have elevated circulating NPY, but do exhibit BIBO3304-sensitive, increased cardiomyocyte intracellular Ca2+. In vivo, this translates to NPY1R antagonism attenuating cardiac calcineurin activity and isoproterenol-induced cardiomyocyte hypertrophy and fibrosis in full-body Nur77-KO mice, but not in CM-KO mice.. The cardioprotective action of Nur77 can be ascribed to both inhibition of circulating NPY levels and to cardiomyocyte-specific modulation of NPY-NPY1R signalling. These results reveal the underlying mechanism of Nur77 as a promising modifier gene in heart failure.

Topics: Adrenal Glands; Animals; Calcineurin; Calcium Signaling; Cardiomegaly; Female; Fibrosis; Humans; Male; Mice, Inbred C57BL; Mice, Knockout; Myocytes, Cardiac; Neuropeptide Y; Nuclear Receptor Subfamily 4, Group A, Member 1; PC12 Cells; Rats; Rats, Wistar; Receptors, Neuropeptide Y; Sympathetic Nervous System; Ventricular Remodeling

Neuropeptide Y (NPY) is coreleased with norepinephrine and stimulates vasoconstriction, vascular and cardiomyocyte hypertrophy via Y1 receptors (R) and angiogenesis via Y2R. Although circulating NPY is elevated in heart failure, NPY's role remains unclear. Activation of the NPY system was determined in Wistar rats with the aortocaval (A-V) fistula model of high-output heart failure. Plasma NPY levels were elevated in A-V fistula animals (115.7 +/- 15.3 vs. 63.1 +/- 17.4 pM in sham, P < 0.04). Animals either compensated [urinary Na(+) excretion returning to normal with moderate disease (COMP)] or remained decompensated with severe cardiac and renal failure (urinary Na(+) excretion <0.5 meq/day), increased heart weight, decreased mean arterial pressure and renal blood flow (RBF), and death within 5-7 days (DECOMP). Cardiac and renal tissue NPY decreased with heart failure, proportionate to the severity of renal complications. Cardiac and renal Y1R mRNA expression also decreased (1.5-fold, P < 0.005) in rats with heart failure. In contrast, Y2R expression increased up to 72-fold in the heart and 5.7-fold in the kidney (P < 0.001) proportionate to severity of heart failure and cardiac hypertrophy. Changes in receptor expression were confirmed since the Y1R agonist, [Leu31, Pro34]-NPY, had no effect on RBF, whereas the Y2R agonist (13-36)-NPY increased RBF to compensate for disease. Thus, in this model of heart failure, cardiac and renal NPY Y1 receptors decrease and Y2 receptors increase, suggesting an increased effect of NPY on the receptors involved in cardiac remodeling and angiogenesis, and highlighting an important regulatory role of NPY in congestive heart failure.

Topics: Animals; Blotting, Northern; Cardiomegaly; Cardiomyopathy, Dilated; Gene Expression; Kidney; Male; Myocardium; Neuropeptide Y; Radioimmunoassay; Rats; Receptors, Neuropeptide Y; Renal Circulation; Sodium

To determine whether neuropeptide Y (NPY)-related mechanisms become activated with progression of cardiac hypertrophy in vivo, protein mass and de novo protein synthesis (incorporation of [(14)C]Phe, 0.1 muCi ml(-1)) were assessed in cardiomyocytes, obtained from spontaneously hypertensive rats (SHRs) and normotensive Wistar Kyoto rats (8, 12, 16, 20, and 24 weeks of age), and cultured for 24 h. NPY (10(-8) M) increased protein mass of cardiomyocytes from 16-week-old SHRs by 9.2 +/- 2.1% (n = 8, P < 0.05). De novo protein synthesis was increased maximally in SHRs at 12, 16, and 20 weeks (P < 0.05, n = 8) in response to NPY by 12.6 +/- 2.1% (10(-6) M), 20.1 +/- 4.2% (10(-8) M), and 9.4 +/- 1.8% (10(-7) M), respectively. Peptide YY(3-36), (PYY(3-36)), which displays selectivity for NPY Y(2) and NPY Y(5) receptors, and the NPY Y(5)-selective agonist [D-Trp(34)]-NPY increased de novo protein synthesis maximally by 16.2 +/- 5.1% (10(-7) M; n = 4, P < 0.05) and 17.8 +/- 5.2% (10(-6) M; n = 7, P < 0.05), respectively, in SHRs at 16 weeks, whereas [Leu(31)Pro(34)]-NPY (< or =10(-6) M), which displays some activity at NPY Y(1) and NPY Y(4) receptors, did not. The NPY Y(1)-selective antagonist BVD-42 (2 x 10(-7) M) and the NPY Y(2)-selective antagonist BIIE0246 (2 x 10(-7) M) did not attenuate responses to NPY (10(-7) M) and PPY(3-36) (10(-7) M). These data indicate that hypertrophic responsiveness to NPY, mediated via NPY Y(5) receptors, is induced transiently in SHR cardiomyocytes subsequent to onset of cardiomyocyte hypertrophy in response to pressure overload.

Topics: Animals; Cardiomegaly; DNA; Female; Heart; Humans; Hypertension; Male; Muscle Proteins; Myocardium; Neuropeptide Y; Phenylalanine; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Neuropeptide Y; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Time Factors; Transforming Growth Factor beta

Topics: Animals; Calcitonin Gene-Related Peptide; Cardiomegaly; Endothelins; Hypertension; Motor Activity; Neuropeptide Y; Rats; Rats, Wistar

Using a transgenic mouse model of myocardial-targeted overexpression of the wild-type alpha1B adrenergic receptor (AR) (Tg alpha43), we studied the role of the betaAR kinase (betaARK1) in the evolution of myocardial hypertrophy and its transition to heart failure (HF).. Increased myocardial expression of betaARK1 has been shown to be associated with HF and certain models of hypertrophy.. Tg alpha43 mice and their nontransgenic littermate controls were treated with the alpha1AR agonist phenylephrine (PE) for 3, 7 or 14 days to characterize the cardiac consequences.. Nontransgenic littermate control mice treated for 14 days with PE display cardiac hypertrophy with no increase in betaARK1 expression. However, Tg alpha43 animals show a reduced tolerance to 14-day PE treatment, demonstrated by reduced survival and severe cardiac hypertrophy. Moreover, PE treatment for three and seven days in Tg alpha43 mice resulted in an exaggerated hypertrophic response accompanied by significant cardiac biochemical abnormalities that are normally associated with HF, including fetal gene expression, reduced betaAR density and enhanced betaARK1 expression. We also found reduced myocardial stores of the sympathetic neurotransmitter neuropeptide Y.. These data suggest that PE-treated Tg alpha43 mice have chronic activation of the cardiac sympathetic nervous system, which may be responsible for the appearance of apparent maladaptive hypertrophy with an evolution towards HF and sudden death. Thus, the cardiac phenotypes found in these mice are not the direct result of enhanced alpha1B AR signaling and suggest that betaARK1 is a key molecule in the transition of myocardial hypertrophy to HF.

Topics: Adrenergic alpha-Agonists; Animals; beta-Adrenergic Receptor Kinases; Body Weight; Cardiomegaly; Cardiomyopathy, Dilated; Cyclic AMP-Dependent Protein Kinases; Mice; Mice, Transgenic; Muscle Proteins; Myocardium; Neuropeptide Y; Organ Size; Phenylephrine; Receptors, Adrenergic, alpha-1; Receptors, Adrenergic, beta; RNA, Messenger; Signal Transduction

Signal transduction pathways involved in the hypertrophic effect of neuropeptide Y (NPY) were investigated in adult cardiomyocytes. Reduction of transforming growth factor-beta activity in serum-supplemented media abolished the induction of hypertrophic responsiveness to NPY. In responsive cells, NPY (100 nM) increased protein synthesis, determined as incorporation of [14C]phenylalanine, by 35 +/- 15% (P < 0.05, n = 16 cultures). In these cells, NPY activated pertussis toxin (PTx)-sensitive G proteins and phosphatidylinositol (PI) 3-kinase. PTx and inhibition of PI 3-kinase abolished the hypertrophic effect of NPY. NPY also activated protein kinase C (PKC) and mitogen-activated protein (MAP) kinase. Inhibition of these two kinases attenuated the induction of creatine kinase (CK)-BB but not the growth response to NPY. In conclusion, NPY stimulates protein synthesis in adult cardiomyocytes via activation of PTx-sensitive G proteins and PI 3-kinase and it induces the fetal-type CK-BB via activation of PKC and MAP kinase.

Topics: Androstadienes; Animals; Aprotinin; Calcium-Calmodulin-Dependent Protein Kinases; Cardiomegaly; Cells, Cultured; Creatine Kinase; Cyclic AMP; Enzyme Activation; Enzyme Induction; Enzyme Inhibitors; GTP-Binding Proteins; Heart; Heart Ventricles; Isoenzymes; Isoproterenol; Male; Models, Cardiovascular; Myocardium; Neuropeptide Y; Pertussis Toxin; Phosphatidylinositol 3-Kinases; Protein Kinase C; Rats; Rats, Wistar; Signal Transduction; Sirolimus; Tetradecanoylphorbol Acetate; Virulence Factors, Bordetella; Wortmannin

In the present study, we investigated serum and myocardial neuropeptide Y concentrations as measures of sympathetic activity as well as myocardial beta-adrenoceptors and beta-adrenoceptor-stimulated adenylyl cyclase activity in spontaneously hypertensive rats (SHR). SHR and control rats at 10 weeks of age were kept on oral treatment with captopril, nitrendipine, or both for 20 weeks. Treatment only slightly reduced but did not normalize blood pressure and cardiac hypertrophy in SHR. The elevated serum concentration of neuropeptide Y, the reduced number of beta-adrenoceptors, and the depressed beta-adrenoceptor-stimulated adenylyl cyclase activity were partly normalized compared with the values observed in control rats. We conclude that antihypertensive treatment, at doses that failed to normalize systolic pressure and to reverse cardiac hypertrophy completely, is able to reduce sympathetic activity in SHR, thereby resensitizing the depressed beta-adrenoceptor-adenylyl cyclase system.

Topics: Adenylyl Cyclases; Animals; Captopril; Cardiomegaly; Hypertension; Male; Myocardium; Neuropeptide Y; Nitrendipine; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Rats, Wistar; Receptors, Adrenergic, beta; Sympathetic Nervous System

We studied neuroeffector defects in hypertrophied myocardium of hypertensive transgenic rats harboring the mouse Ren-2d gene. In transgenic rats, epinephrine and neuropeptide Y concentrations were reduced. A heterologous desensitization of adenylyl cyclase was observed, which was accompanied by a downregulation of beta 1-adrenergic receptors, an increase of inhibitory G protein alpha-subunits, and a mildly depressed catalyst activity of adenylyl cyclase, whereas the bioactivity of stimulatory G protein alpha-subunits and beta 2-adrenergic receptors was unchanged. Desensitization of adenylyl cyclase was accompanied by a reduced positive inotropic response to isoproterenol, whereas the effect of Ca2+ was unchanged. We conclude that sympathetic neuroeffector defects occur in transgenic rats similar to those observed in human failing myocardium. These alterations occur in the stage of hypertrophy and could contribute to contractile dysfunction in later stages.

Topics: Adenylyl Cyclases; Animals; Animals, Genetically Modified; Cardiomegaly; GTP-Binding Proteins; Myocardial Contraction; Myocardium; Neuroeffector Junction; Neuropeptide Y; Norepinephrine; Osmolar Concentration; Rats; Receptors, Adrenergic, beta; Renin

We investigated neurohumoral profiles and transmitter and neuroenzyme markers of cardiac autonomic innervation in control (unpaced) dogs and three groups of dogs with pacing-induced heart failure (paced, paced + beta-adrenergic blockade, and paced + cardiac denervation). Left ventricular ejection fraction decreased significantly and to a comparable extent in all paced groups. Pacing increased plasma norepinephrine (NE); increases in NE were not attenuated but instead tended to be exaggerated by treatment with propranolol or cardiac denervation. Atrial hypertrophy occurred in all paced groups compared with the control group. However, atrial and right ventricular hypertrophy were not as pronounced in the paced plus cardiac denervation group as in the paced and paced plus propranolol groups. Pacing also depleted neuropeptide Y and NE from all heart chambers; propranolol treatment did not modify these local tissue changes. Pacing caused selective depletion of neuroenzymes predominantly in the left ventricle; again, propranolol did little to modify these changes. In this study of paced animals with experimentally maintained cardiac dysfunction, failure to modify noradrenergic responses with intrapericardial cardiac denervation suggests that noncardiac sources contribute predominantly to high plasma NE. Failure to modify neurohumoral, neuropeptide, and neuroenzyme responses with beta-antagonist suggests this treatment has little practical direct influence on sympathetic vasomotor activity or neuronal function in heart failure.

Topics: Animals; Arginine Vasopressin; Atrial Natriuretic Factor; Bicarbonates; Biomarkers; Body Weight; Cardiac Pacing, Artificial; Cardiomegaly; Dogs; Electric Stimulation; Electrolytes; Heart; Heart Failure; Muscle Denervation; Neuropeptide Y; Neuropeptides; Norepinephrine; Oxygen; Partial Pressure; Propranolol; Reference Values; Respiration; Vagus Nerve; Ventricular Function, Left

To clarify whether central catecholamine systems are modulated by neuropeptide Y (NPY) soon after imposing an increased pressure overload on the heart. Recent evidence supports the view that the sympathetic nervous system actively participates in the development of cardiac hypertrophy. Since noradrenaline-containing neurons involved with cardiovascular regulation within the brain are known to coexist with NPY, it is possible that a functional interaction between NPY and noradrenaline exists centrally.. The paraventricular nucleus (PVN) of aortic-banded Sprague-Dawley rats were sampled for noradrenaline levels using in vivo microdialysis and compared with samples taken from sham-operated controls. Autoradiographical localization of NPY receptors in the PVN was also carried out between animal groups.. Forty-eight Sprague-Dawley rats (weighing between 175 and 200 g).. The 48 rats were randomly divided into two groups. One group underwent abdominal suprarenal aortic constriction. The control group underwent the same procedure without being banded. At 14 days postsurgery, the animals had microdialysis probes stereotaxically implanted into the PVN under anesthesia. A solution of NPY (10(-8) M) was perfused through the probe for 20 mins, and catecholamine levels were measured in the resulting perfusate.. Extracellular noradrenaline concentrations in the PVN were found to be increased following aortic constriction compared with sham controls (P < 0.05). Infusion of NPY resulted in a reduction of noradrenaline concentration in sham animals (P < 0.05), whereas no change in noradrenaline concentration was evident in the aortic-constricted group. Autoradiography of NPY receptors in the PVN showed a significant decrease in the receptor density in aortic-constricted rats versus sham controls (P < 0.05).. The results strongly support the view that NPY plays an important neuromodulatory role in the PVN regarding control of sympathetic output. It is suggested that cardiac hypertrophy may be precipitated secondary to changes in brain NPY levels and increased sympathetic activity.

Topics: Animals; Aorta; Autoradiography; Cardiomegaly; Constriction; Male; Neuropeptide Y; Norepinephrine; Paraventricular Hypothalamic Nucleus; Rats; Rats, Sprague-Dawley; Receptors, Neuropeptide Y

It was investigated whether neuropeptide Y (NPY) could exert a trophic effect on ventricular myocytes isolated from the adult rat heart. Two different culture models were used: day 1 and 7 cultures of cardiomyocytes. In day 1 and 7 cultures, NPY caused an increase in cellular protein mass. In day 1 cultures, NPY (10 nM) increased the protein-to-DNA ratio within 24 h by 10.1 +/- 2.8% (P < 0.01), but did not stimulate the incorporation of [14C]phenylalanine into cell proteins. The degradation of proteins was retarded in presence of NPY, revealed by pulse-chase experiments. In day 7 cultures, NPY (10 nM) increased the protein-to-DNA ratio within 24 h by 33.9 +/- 5.0% (P < 0.01), increased the RNA-to-DNA ratio by 19.2 +/- 6.4%, and stimulated the incorporation of [14C]phenylalanine by 45.5 +/- 4.5% (P < 0.01). As in day 1 cultures, protein degradation was retarded. The specific activities of cytosolic creatine kinase and lactate dehydrogenase were increased in presence of NPY. This study demonstrates for the first time that NPY is a trophic factor for cardiomyocytes. NPY can cause an increase in cellular mass of protein, i.e., hypertrophy, by two mechanisms: 1) reduction of degradation of protein, found in day 1 and 7 cultures, and 2) stimulation of protein synthesis, observed only in day 7 cultures. The responsiveness of protein synthesis to NPY stimulation is induced during prolonged incubation in culture.

Topics: Animals; Cardiomegaly; Cells, Cultured; Creatine Kinase; Cytosol; DNA; Heart; Kinetics; L-Lactate Dehydrogenase; Male; Methionine; Myocardium; Neuropeptide Y; Protein Biosynthesis; Proteins; Rats; Rats, Wistar; Time Factors

Several observations now support the view that the sympathetic system actively participates in the development of cardiac hypertrophy. Since norepinephrine (NE)-containing neurons involved in cardiovascular regulation in the brain are known to coexist with neuropeptide Y (NPY), it is possible that a functional interaction between NPY and NE exists centrally. In an effort to clarify whether or not central catecholamine systems are modulated by NPY soon after imposing an increased pressure overload on the heart, male Sprague-Dawley rats underwent aortic constriction and were examined 14 days later. Rats were anesthetized and subjected to microdialysis sampling by stereotaxically implanting a probe into the caudal ventrolateral medulla (A1). Perfusate was collected after a 1-hour stabilization period, purified, and analyzed for interstitial concentrations of NE and other catecholamines using high-performance liquid chromatography with an electrochemical detector. Extracellular NE concentrations in the A1 area were found to be decreased. These results were associated with increased rate of change in the specific activity of NE (NE turnover) in heart, indicating increased sympathetic activity and an increased left ventricular weight. Also, infusion of NPY (10(-9) mol/L) by microdialysis in the A1 area resulted in the reduction of NE concentration; epinephrine and dopamine levels were also decreased. In contrast, methionine-enkephalin, another neuropeptide, had no effect on the extracellular catecholamine concentrations in the A1 area. Since neurons of the A1 group project almost exclusively to forebrain structures inhibiting sympathetic activity, it is concluded that decreases of NE and other catecholamines in afferent pathways regulating the caudal ventrolateral medulla may lead to an enhanced sympathetic activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Brain Chemistry; Cardiomegaly; Catecholamines; Enkephalin, Methionine; Male; Medulla Oblongata; Neuropeptide Y; Norepinephrine; Rats; Rats, Inbred Strains