Adrenal medulla denervation prevents stress-induced epinephrine plasma elevation and cardiac hypertrophy

Circulating catecholamines have been proposed as trophic agents for the heart. Denervation of the adrenal medullae, the major source of plasma epinephrine, totally blocked left ventricular hypertrophy after aortic coarctation in the dog. The level of epinephrine after adrenal medullary cholinergic denervation dropped to a mean of 10 pg/ml within 48 hours compared to 317 pg/ml in coarcted dogs with intact adrenal innervation, and 116 pg/ml in sham-coarcted controls. Decreased epinephrine levels were concomitant with a decrease in the heart weight to body weight ratios. These data implicate epinephrine as the specific hormone regulating cardiac hypertrophy.     

Elevated blood pressure and cardiac hypertrophy after ablation of the gly96/IEX-1 gene.

gly96/IEX 1 is a growth- and apoptosis-regulating, immediate early gene that is widely expressed in epithelial and vascular tissues. In vascular tissues, expression of the gene is induced by mechanical stretch, and overexpression of the gene prevents injury-induced vascular smooth muscle hypertrophy and neointimal hyperplasia. We now show that deletion of the gly96/IEX-1 gene in mice is associated with development of elevated blood pressure, cardiac hypertrophy, and diminished fractional shortening of the left ventricle. Systolic blood pressure in conscious male gly96/IEX-1-/- mice is 20-25 mmHg higher than in gly96/IEX-1+/+ mice. Serum and/or urine concentrations of sodium, potassium, creatinine, angiotensin II, corticosterone, aldosterone, epinephrine, norepinephrine, prostaglandin E2, thromboxane B2, prostaglandin-6-keto-1alpha, nitrites and nitrates, cAMP, and cGMP are normal in gly96/IEX-1-/- mice. Alterations in dietary sodium intake do not alter blood pressure in gly96/IEX-1-/- mice. Aortic mRNAs for endothelial nitric oxide synthase, guanylate cyclase-alpha, and cGMP kinase-1 are increased in gly96/IEX-1-/- mice. Treatment with Nomega-nitro-L-arginine methyl ester or L-arginine does not alter blood pressure in gly96/IEX-1-/- mice. Gly96/IEX-1-/- mice respond to infused sodium nitroprusside with decrements in blood pressure similar to those seen in wild-type littermate mice. In contrast to gly96/IEX-1 transgenic mice that have abnormalities in immune function, gly96/IEX-1-/- mice have normal lymphoid tissue architecture and a normal complement of T and B cells in lymphoid tissues. Ablation of the gly96/IEX-1 gene results in hypertension and cardiac hypertrophy, suggesting a novel role for this gene in cardiovascular physiology.     

Hemodynamic physiology and thermoregulation in liposuction

Little is known about the physiology of large-volume liposuction. Patients are exposed to prolonged procedures, general anesthesia, fluid shifts, and infusion of high doses of epinephrine and lidocaine. Consequently, the authors examined the thermoregulatory and cardiovascular responses to liposuction by assessing multiple physiologic factors. The aims of their study were to serially determine hemodynamic parameters perioperatively, to quantify perioperative and postoperative plasma epinephrine levels, and to chronologically document fluctuations in core body temperature. Five female volunteers with American Society of Anesthesiologists' physical status I and II underwent moderate- to large-volume liposuction. Heart rate, blood pressure, mean pulmonary arterial pressure, cardiac index, and central venous pressure were monitored. Serum epinephrine levels and core body temperature were assessed perioperatively. The hemodynamic responses to liposuction were characterized by an increase in cardiac index (57 percent), heart rate (47 percent), and mean pulmonary arterial pressure (44 percent) (p < 0.05). Central venous pressure was not significantly altered. Maximum epinephrine levels were observed 5 to 6 hours after induction. Significant correlations between cardiac index and epinephrine concentrations were shown intraoperatively (r = 0.75). All patients developed intraoperative low body temperatures (mean 35.5 degrees C). An overall enhanced cardiac function was observed in patients subsequent to large-volume liposuction. The etiology of the altered cardiac parameters was multifactorial but may have been attributable in part to the administration of epinephrine, which counters the effects of general anesthesia and operative hypothermia. Additional explanations for raised cardiac output may be hemodilution or emergence from general anesthesia. Elevated mean pulmonary arterial pressure may be a result of subclinical fat embolism demonstrated in previous porcine studies, although fat was not observed in urine. The unchanged central venous pressure levels indicate that young healthy patients with compliant right ventricles can accommodate the fluid loads of large-volume liposuction. Overall hemodynamic parameters remained within safe limits. Within these surgical parameters, patients should be clinically screened for cardiovascular and blood pressure disorders before liposuction is undertaken, and preventative measures should be taken to limit intraoperative hypothermia.     

Pharmacokinetics and safety of epinephrine use in liposuction

Patients are routinely exposed to high-dose epinephrine infiltration during large-volume liposuction. Because of the serious cardiovascular side-effect profile of catecholamine overdose, the authors examined the safety of larger-volume liposuction by assessing epinephrine pharmacokinetics. Five female volunteers with American Society of Anesthesiologists physical status of I or II, aged 29 to 40 years and weighing 75.9 to 95 kg, underwent liposuction. The wetting solution contained 7.3 mg (SEM, 0.7 mg) of epinephrine, corresponding to 0.09 mg/kg (0.04 mg/kg). Total plasma epinephrine and norepinephrine concentrations were assessed by high-performance liquid chromatography. Approximate exogenous epinephrine absorption was calculated after correction for estimated endogenous epinephrine production. Pharmacokinetic assessments were performed using standard equations. The total plasma epinephrine peak occurred at the final intraoperative reading (5 hours after induction) and was 323 pg/ml (24.8 pg/ml), three to four times maximum baseline resting levels. The norepinephrine level was slightly elevated throughout the study period, with a reversal of the normal epinephrine/norepinephrine ratio (<0.5:1) demonstrated intraoperatively (>5:1). Estimated time to peak exogenous epinephrine level ranged from 1 to 4 hours from the start of infiltration. Area under the plasma concentration versus time curve was approximately 2089 to 2610 pg x hour/ml. Peak exogenous epinephrine concentration was estimated to be 286 to 335 pg/ml. Clearance was 764,508 ml/hour and volume of distribution was 0.4 liter/kg (0.006 liter/kg). Total absorbed epinephrine was estimated, 1.8 mg to 2.2 mg, equivalent to 25 to 32 percent of the infiltrated dose. The reversal of the normal epinephrine/norepinephrine ratio and the fact that norepinephrine levels were within normal range implied that the majority of plasma epinephrine measured was exogenously infiltrated and not endogenously synthesized. On the basis of these observations, pharmacokinetic analyses were performed. Although unequivocal toxic epinephrine levels were not demonstrated, epinephrine peaks were three to four times the maximum observed in normal resting patients. Peak levels were comparable to those observed during major physiologic stresses, such as exercising to exhaustion, open abdominal surgery, or cross-clamping the aorta during surgical repair. Furthermore, epinephrine has been associated with myocardial infarction, arrhythmias, and fatal asystole in susceptible patients at these levels. Patients should be carefully screened for clinical evidence of hemodynamic and cardiac pathology before larger-volume liposuction is undertaken, as it may result in unnecessary high risk for patients who have preexisting cardiovascular disorders. Healthy American Society of Anesthesiologists physical status I or II patients should have sufficient cardiac reserve to tolerate these catecholamine levels.     

The antidysrhythmic effect of metoprolol in the epinephrine treated chick embryo

It was confirmed through electrocardiography that within two hours after epinephrine treatment, four day chick embryos either maintained normal rhythm or developed a severe cardiac dysrhythmia (22/93, 24% dysrhythmic). The ECG dysrhythmia in epinephrine treated embryos were characterized by periods of bradycardia, asystole, and various supraventricular or ventricular dysrhythmias. Within four hours after treatment, dysrhythmic embryos either reestablished normal rhythmicity or died. Electrocardiographic data also demonstrated that metoprolol pretreatment will block epinephrine induced dysrhythmias (0/46, 0% dysrhythmic). We conclude that metoprolol possesses antidysrhythmic properties in the epinephrine treated chick embryo.     

Gender differences in β‐adrenoceptor system in cardiac hypertrophy due to arteriovenous fistula

This study was undertaken to determine alterations in the β‐adrenoceptor (β‐AR) signaling system in male and female rats at 4 weeks after the induction of arteriovenous (AV) fistula or shunt. AV shunt produced a greater degree of cardiac hypertrophy and larger increase in cardiac output in male than in female animals. Increases in plasma levels of norepinephrine and epinephrine (EPI) due to AV shunt were also higher in male than females. While no difference in the β₁‐AR affinity was seen in males and females, AV shunt induced increase in β₁‐AR density in female rats was higher than that in males. Furthermore, no changes in basal adenylyl cyclase (AC) V/VI mRNA levels were seen; however, the increase in EPI‐stimulated AC activities was greater in AV shunt females than in males. AV shunt decreased myocardial β₁‐AR mRNA level in male rats and increased β₂‐AR mRNA level in female hearts; an increase in G_i‐protein mRNA was detected only in male hearts. Although GRK2 gene expression was increased in both sexes, an increase in GRK3 mRNA was seen only in AV shunt female rats. β‐arrestin1 mRNA was elevated in females whereas β‐arrestin 2 gene expression was increased in both male and female AV shunt rats. While these data demonstrate gender associated differences in various components of the β‐AR system in cardiac hypertrophy due to AV shunt, only higher levels of plasma catecholamines may account for the greater increase in cardiac output and higher degree of cardiac hypertrophy in males. J. Cell. Physiol. 226: 181–186, 2010. © 2010 Wiley‐Liss, Inc.     

Ventricular blood pressure and cardiac output changes in epinephrine- and metoprolol-treated chick embryos

The effects of a teratogenic dose (5 micrograms) of epinephrine on mean ventricular blood pressure (MVBP) and cardiac output (CO) at one and two hours after treating stage 24 chick embryos were investigated. Previous work demonstrated that a differential response in terms of cardiac rhythm during the first hour after epinephrine treatment was related to pathogenesis of two contrasting types of aortic arch malformations. Absence of one or more aortic arches occurred more frequently in embryos which developed a characteristic dysrhythmia, while persistence of the left fourth aortic arch (PL4AA) occurred more frequently in nondysrhythmic embryos. In this study, dysrhythmic epinephrine-treated embryos exhibited reductions in both MVBP and CO at one hour after treatment when compared to control values. Nondysrhythmic epinephrine-treated embryos exhibited elevated MVBP and no change in CO at one hour after treatment. MVBP and CO in recovered dysrhythmic and nondysrhythmic embryos were similar to control values at two hours following epinephrine treatment. MVBP and CO measurements were obtained from embryos which were pretreated with metoprolol and then subsequently treated with epinephrine. Metoprolol is a beta 1-adrenoreceptor antagonist which was previously shown to block the teratogenic effects of epinephrine and other catecholamines with beta 1-adrenoreceptor agonist properties. Pretreating embryos with metoprolol in this study reduced the dysrhythmogenic potential of epinephrine and also blocked the MVBP and CO changes observed in embryos treated with epinephrine alone. We conclude that pathogenesis of 1) abnormally absent aortic arches is related to dysrhythmogenesis, reduced MVBP, and reduced CO, and 2) an abnormally persistent left fourth aortic arch is related to elevated MVBP in the epinephrine model.     

Long‐term administration of pyridostigmine attenuates pressure overload‐induced cardiac hypertrophy by inhibiting calcineurin signalling

Cardiac hypertrophy is associated with autonomic imbalance, characterized by enhanced sympathetic activity and withdrawal of parasympathetic control. Increased parasympathetic function improves ventricular performance. However, whether pyridostigmine, a reversible acetylcholinesterase inhibitor, can offset cardiac hypertrophy induced by pressure overload remains unclear. Hence, this study aimed to determine whether pyridostigmine can ameliorate pressure overload‐induced cardiac hypertrophy and identify the underlying mechanisms. Rats were subjected to either sham or constriction of abdominal aorta surgery and treated with or without pyridostigmine for 8 weeks. Vagal activity and cardiac function were determined using PowerLab. Cardiac hypertrophy was evaluated using various histological stains. Protein markers for cardiac hypertrophy were quantitated by Western blot and immunoprecipitation. Pressure overload resulted in a marked reduction in vagal discharge and a profound increase in cardiac hypertrophy index and cardiac dysfunction. Pyridostigmine increased the acetylcholine levels by inhibiting acetylcholinesterase in rats with pressure overload. Pyridostigmine significantly attenuated cardiac hypertrophy based on reduction in left ventricular weight/body weight, suppression of the levels of atrial natriuretic peptide, brain natriuretic peptide and β‐myosin heavy chain, and a reduction in cardiac fibrosis. These effects were accompanied by marked improvement of cardiac function. Additionally, pyridostigmine inhibited the CaN/NFAT3/GATA4 pathway and suppressed Orai1/STIM1 complex formation. In conclusion, pressure overload resulted in cardiac hypertrophy, cardiac dysfunction and a significant reduction in vagal discharge. Pyridostigmine attenuated cardiac hypertrophy and improved cardiac function, which was related to improved cholinergic transmission efficiency (decreased acetylcholinesterase and increased acetylcholine), inhibition of the CaN/NFAT3/GATA4 pathway and suppression of the interaction of Orai1/STIM1.     

Myocardial hypertrophy, cardiac and urinary catecholamines during severe ethanol intoxication and withdrawal

Cardiomegaly was observed in rats severely intoxicated with ethanol for a 4 day period. It was apparent at 48 hours of treatment, a time at which cardiac protein was elevated and continued into withdrawal. During a 4 day abstinence period the degree of hypertrophy declined towards normal. Cardiac noradrenaline was reduced at the 48 hour time of intoxication, then increased gradually in the further experimental period. As the cardiac hypertrophy occurs at a time that urinary catecholamines are elevated and the adrenal medulla is intensely stimulated, it is proposed that increased levels of circulating catecholamines are largely responsible for the enlargement of the heart.     

Cardiac volume overload rapidly induces oxidative stress-mediated myocyte apoptosis and hypertrophy

Oxidative stress stimulates both growth and apoptosis in cardiac myocytes in vitro. We investigated the role of oxidative stress in the initial phases of cardiac remodeling induced in an animal model by volume overload. As plausible candidates for a connection between oxidative stress and cardiomyocyte apoptosis or hypertrophy, we explored the behaviour of two MAPKs, specifically JNK and ERK. At 48 h of overload, the greatest increase in oxidative stress coincided with a peak of cardiomyocyte apoptosis. This was possibly induced through the mitochondrial metabolism, as evidenced by the release of cytochrome c and a significant increase in the active forms of caspase-9 and -3, but not caspase-8. Oxidative stress markers significantly decreased at 96 h of overload, combined with a marked attenuation of apoptosis and the appearance of hypertrophy. The highest levels of JNK and the lowest levels of ERK phosphorylation were observed at 48 h of overload. Conversely, a sharp increase in ERK phosphorylation was detected at 96 h of overload coinciding with the hypertrophic response. Together these results show that oxidative stress is an early and transient event in myocardial volume overload. They suggest that oxidative stress mediates amplitude dependent apoptotic and hypertrophic responses in cardiomyocytes through the selective activation of, respectively, JNK and ERK.     

Evaluation of plasma norepinephrine as an index of sympathetic neuron function in the conscious, unrestrained rat.

Measurement of plasma norepinephrine and epinephrine concentrations in the conscious, unrestrained rat yielded values of 138±10 and 55±8 pg/ml, respectively. Ganglionic blockade reduced basal norepinephrine levels without affecting plasma epinephrine levels. Adrenal demedullation reduced plasma epinephrine to undetectable levels (<20 pg/ml) and gave rise to an apparent compensatory increase in plasma norepinephrine levels. Adrenal demedullation in combination with ganglionic blockade reduced plasma norepinephrine to the same level as did ganglionic blockade alone. These observations indicated that the plasma epinephrine was of adrenal origin. Furthermore, under these experimental conditions, the results suggested that the major portion of the plasma norepinephrine was of neuronal origin. When specific destruction of the sympathetic nerve terminals without alteration of adrenal medullary function was accomplished with 6-hydroxydopamine, a fivefold increase in plasma epinephrine concentration was observed at 24 hours. Plasma norepinephrine levels at 24 hours were not significantly altered from the control levels by the 6-hydroxydopamine suggesting that the rodent adrenal medulla was capable of secreting substantial amounts of norepinephrine under these conditions. It was concluded that plasma norepinephrine concentrations reflect both sympathetic neuronal and adrenomedullary activity. However, in the absence of changes in plasma epinephrine, plasma norepinephrine appears to be an index of sympathetic neuron function.     

Alterations in activities of cyclic nucleotide systems and in beta-adrenergic receptor-mediated activation of cyclic AMP-dependent protein kinase during progression and regression of isoproterenol-induced cardiac hypertrophy.

Initial and transient increases in the basal levels of cyclic GMP in the heart were noted prior to cardiac hypertrophy in rats administered isoproterenol. Increased levels of cyclic AMP-phosphodiesterase (in both the soluble and particulate fractions) and stimulatory modulator of cyclic GMP-dependent protein kinase, however, were associated with the progression, or the state, of cardiomegaly, with their levels returning to the control values upon regression of the hypertrophy. The levels of cyclic GMP phosphodiesterase in the soluble fraction were lower, whereas those in the particulate fraction were higher, in the hypertrophied heart than the control. In cardiac hypertrophy, the maximal activity ratio(--cyclic AMP/+cyclic AMP) of cyclic AMP-dependent protein kinase in the incubated minced heart caused by isoproterenol was lower, whereas the concentration of isoproterenol required to increase the activity ratio half-maximally was higher than controls; the reduced responsiveness to the drug, however, was reversed when the hypertrophy regressed. These observations, taken collectively, appear to suggest that the desensitization of the beta-adrenergic mechanism seen in the cardiac hypertrophy produced by repeated administration of isoproterenol is associated with adaptive modifications in certain parameters of the cyclic nucleotide systems.     

Cell Hypertrophy and MEK/ERK Phosphorylation are Regulated by Glyceraldehyde-Derived AGEs in Cardiomyocyte H9c2 Cells

Diabetic cardiomyopathy has been shown to promote hypertrophy, leading to heart failure. Recent studies have reported a correlation between diabetic cardiomyopathy and oxidative stress, suggesting that the accumulation of advanced glycation end products (AGEs) induces the production of reactive oxygen species (ROS). In a clinical setting, AGEs have been shown to increase the risk of cardiovascular disease; however, the relationship between AGEs and cardiac hypertrophy remains unclear. This study sought to identify the role of AGEs in cardiac hypertrophy by treating H9c2 cells with glyceraldehyde-derived AGEs (200 μg/ml) or H₂O₂ (50 μM) for 96 h. Our results demonstrate that AGEs significantly increased protein levels and cell size. These effects were effectively blocked with PD98059 (10 μM; MEK/ERK inhibitor) pretreatment, suggesting that AGEs caused cell hypertrophy via the MEK/ERK pathway. We then treated cells with AGEs and H₂O₂ for 0–120 min and employed the Odyssey infrared imaging system to detect MEK/ERK phosphorylation. Our results show that AGEs up-regulated MEK/ERK phosphorylation. However, this effect was blocked by NAC (5 mM; ROS inhibitor), indicating that AGEs regulate MEK/ERK phosphorylation via ROS. Our findings suggest that glyceraldehyde-derived AGEs are closely related to cardiac hypertrophy and further identify a molecular mechanism underlying the promotion of diabetic cardiomyopathy by AGEs.     

Alterations in activities of cyclic nucleotide systems and in β-adrenergic receptor-mediated activation of cyclic amp-dependent protein kinase during progression and regression of isoproterenol-induced cardiac hypertrophy

Initial and transient increases in the basal levels of cyclic GMP in the heart were noted prior to cardiac hypertrophy in rats administered isoprotenol. Increased levels of cyclic AMP-phosphodiesterase (in both the soluble and particulate fractions) and stimulatory modulator of cyclic GMP-dependent protein kinase, however, were associated with the progression, or the state, of cardiomegaly, with their levels returning to the control values upon regression of the hypertrophy. The levels of cyclic GMP phosphodiesterase in the soluble fraction were lower, whereas those in the particulate fraction were higher, in the hypertrophied heart than the control. In cardiac hypertrophy, the maximal activity ratio (?cyclic AMP/+cyclic AMP) of cyclic AMP-dependent protein kinase in the incubated minced heart caused by isoproterenol was lower, whereas the concentration of isoproterenol required to increase the activit ratio half-maximally was higher than controls; The reduced responsiveness to the drug, however, was reversed when the hypertrophy regressed. These observations, taken collectively, appear to suggest that the desensitization of the β-adrenergic mechanism seen in the cardiac hypertrophy produced by repeated administration of isoproterenol is associated with adaptive modifications in certain parameters of the cyclic nucleotide systems.     

Gender related alterations of β-adrenoceptor mechanisms in heart failure due to arteriovenous fistula

This study was undertaken to determine gender related changes in different components of β-adrenoceptor (β-AR) system in response to arteriovenous fistula (AV-shunt), which is known to produce heart failure due to volume overload. AV-shunt was induced in male and female rats for 16 weeks by the needle technique; ovariectomized (OVX) rats treated with or without estrogen were also used. Although AV-shunt for 16 weeks produced cardiac hypertrophy in both sexes, male animals showed cardiac dysfunction whereas cardiac performance was maintained in females. Both β(1) -AR and β(2) -AR protein content and mRNA levels were decreased in male and increased in female hearts post-AV-shunt. The basal adenylyl cyclase (AC) activity was lower in the female heart; however, AC protein content and the increase in epinephrine (EPi)-stimulated AC activity were greater in the female AV-shunt group as compared to males. While AC V/VI and β-arrestin 2 mRNA levels were decreased in males, mRNA level for GRK2 was increased in females post-AV-shunt. In contrast to intact females, AV-shunt OVX animals showed depressed cardiac function, decreased β(1) -AR, β(2) -AR, and AC protein content, as well as reduced EPi-stimulated AC activity. Treatment of OVX rats with 17-β estradiol attenuated the AV-shunt induced changes in β-AR and AC protein content as well as cardiac dysfunction. These results reveal that β-AR signal transduction system in response to AV-shunt is downregulated in males and upregulated in females. Furthermore, estrogen appears to play an important role in the upregulation of β-AR mechanisms and the maintenance of cardiac function in AV-shunt females.     

Differential Effects of Hypoxic and Hyperoxic Stress-Induced Hypertrophy in Cultured Chick Fetal Cardiac Myocytes

The adult heart responds to contraction demands by hypertrophy, or enlargement, of cardiac myocytes. Adaptive hypertrophy can occur in response to hyperoxic conditions such as exercise, while pathological factors that result in hypoxia ultimately result in heart failure. The difference in the outcomes produced by pathologically versus physiologically induced hypertrophy suggests that the cellular signaling pathways or conditions of myocytes may be different at the cellular level. The structural and functional changes in myocytes resulting from hyperoxia (simulated using hydrogen peroxide) and hypoxia (using oxygen deprivation) were tested on fetal chick cardiac myocytes grown in vitro. Structural changes were measured using immunostaining for α-sarcomeric actin or MyoD, while functional changes were assessed using immunostaining for calcium/calmodulin-dependent kinase (CaMKII) and by measuring intracellular calcium fluxes using live cell fluorescence imaging. Both hypoxic and hyperoxic stress resulted in an upregulation of actin and MyoD expression. Similarly, voltage-gated channels governing myocyte depolarization and the regulation of CaMK were unchanged by hyperoxic or hypoxic conditions. However, the dynamic features of calcium fluxes elicited by caffeine or epinephrine were different in cells subjected to hypoxia versus hyperoxia, suggesting that these different conditions differentially affect components of ligand-activated signaling pathways that regulate calcium. Our results suggest that changes in signaling pathways, rather than structural organization, may mediate the different outcomes associated with hyperoxia-induced versus hypoxia-induced hypertrophy, and these changes are likely initiated at the cellular level.     

大鼠不同心肌肥厚模型左心室基因表达谱变化的比较

为了解心肌肥厚时基因表达谱的变化规律,本实验复制了三种大鼠心肌肥厚模型：肾上腹主动脉缩窄(suprarenal abdominal aortic stenosis,SRS)、动静脉瘘(arterial-vein fistula,AVF)和去甲。肾上腺素持续静脉输注(jugular vein infusion of norepinephrine,NEi),并应用组织化学方法和超声心动术检测大鼠心脏结构和功能指标,应用cDNA基因芯片技术检测心脏基因表达水平的变化。SRS和NEi引起大鼠向心性心肌肥厚,AVF引起大鼠离心性心肌肥厚,其中NEi大鼠心肌纤维化明显。对不同心肌肥厚模型间大鼠左心室基因表达谱的变化进行两两比较。结果显示,有部分基因在不同模型中表达水平均发生变化,其中多数基因在两种模型中表达水平改变的方向相同,也有少部分基因在两种模型中表达水平改变方向相反。综合比较三种心肌肥厚模型的基因表达谱,各种模型都有特异的基因表达变化,但是有19个基因在三种心肌肥厚模型中表达水平均发生改变。研究结果有可能成为心肌肥厚的标志性基因或治疗靶点,为心肌肥厚发生机制的深入研究提供了新的线索。     

Attenuation of cardiac hypertrophy in carnitine-deficient juvenile visceral steatosis (JVS) mice achieved by lowering dietary lipid

We examined the development of cardiac hypertrophy in juvenile visceral steatosis (JVS) mice, a model of systemic carnitine deficiency, by varying the amount of lipid in the diet. Cardiac hypertrophy was markedly attenuated by decreasing soy bean oil (SBO) from 5% (w/w) to 1%. Triglyceride contents of the ventricles of JVS mice fed 1% SBO were significantly lower than in JVS mice fed 5% SBO. The addition of medium-chain triglycerides metabolically utilized by JVS mice did not affect the development of cardiac hypertrophy. On the other hand, the mRNA levels of atrial natriuretic peptide and skeletal alpha-actin, which are related to cardiac hypertrophy, were also attenuated by decreasing lipid in the diet. Adenylate energy charge and creatine phosphate in the heart of JVS mice at the early stage of hypertrophy were not significantly different from control mice given the same laboratory chow (4.6% of lipid). Although urinary prostaglandin F(2alpha) levels were found to be increased in JVS mice at 15 days of age when they developed cardiac hypertrophy, administration of aspirin was not efficacious. We, therefore, propose that the proportion of lipid in the diet is important in the development of cardiac hypertrophy in carnitine-deficient JVS mice, and that this is not related to prostaglandin formation.