Impaired IGF-I signalling of hypertrophic hearts in the developmental phase of hypertension in genetically hypertensive rats

Insulin-like growth factor-I (IGF-I) signalling is reported to contribute to the modulation of blood pressure and set survival and hypertrophic responses in cardiac tissue. However, whether IGF-I signalling normally acts in cardiac tissues of hypertensive rats is unknown. In this study, using spontaneously hypertensive rats (SHR) and stroke-prone spontaneously hypertensive rats (SPSHR), both with early blood pressure increases, and Wistar-Kyoto (WKY) rats as controls, we measured the hypertrophic and IGF-I signalling activity changes in rat hearts at 4, 6 and 12 weeks of age. Both SHR and SPSHR were found to have significantly increased blood pressures and ratios of heart- and left ventricle- to body weight at 12 weeks of age. However, IGF-IR and its downstream signalling, including the protein levels of PI3K and phosphorylated Akt, known to maintain physiological cardiac hypertrophy and cardiomyocyte survival, were downregulated. The results of dot blotting showed that cardiac mRNA levels of IGF-I in hypertensive rats were higher than those in controls starting from the age of 4 weeks. This difference suggests the increased ligand IGF-I mRNA levels may be a compensatory response caused by the impaired IGF-I signalling. Moreover, enhanced cardiac cytosolic cytochrome-c, a mitochondria-dependent apoptotic pathway component, tended to occur in both hypertensive rats, although it did not reach a significant level. These findings indicate that impaired IGF-IR signalling occurs at early stages, and it may contribute, at least partially, to the development of hypertension and pathological cardiac hypertrophy and to cardiomyocyte apoptosis at later stages in SHR and SPSHR.     

Is the failing heart out of fuel or a worn engine running rich? A study of mitochondria in old spontaneously hypertensive rats

Hypertension now affects about 600 million people worldwide and is a leading cause of death in the Western world. The spontaneously hypertensive rat (SHR), provides a useful model to investigate hypertensive heart failure (HF). The SHR model replicates the clinical progression of hypertension in humans, wherein early development of hypertension is followed by a long stable period of compensated cardiac hypertrophy that slowly progresses to HF. Although the hypertensive failing heart generally shows increased substrate preference towards glucose and impaired mitochondrial function, the cause-and-effect relationship between these characteristics is incompletely understood. To explore these pathogenic processes, we compared cardiac mitochondrial proteomes of 20-month-old SHR and Wistar-Kyoto controls by iTRAQ-labelling combined with multidimensional LC/MS/MS. Of 137 high-scoring proteins identified, 79 differed between groups. Changes were apparent in several metabolic pathways, chaperone and antioxidant systems, and multiple subunits of the oxidative phosphorylation complexes were increased (complexes I, III and IV) or decreased (complexes II and V) in SHR heart mitochondria. Respiration assays on skinned fibres and isolated mitochondria showed markedly lower respiratory capacity on succinate. Enzyme activity assays often also showed mismatches between increased protein expression and activities suggesting elevated protein expression may be compensatory in the face of pathological stress.     

Kallikrein gene delivery attenuates cardiac remodeling and promotes neovascularization in spontaneously hypertensive rats

Hypertension that results in left ventricular (LV) hypertrophy and/or fibrosis can lead to cardiac dysfunction. Spontaneously hypertensive rats (SHR) develop high blood pressure and LV hypertrophy at an early age and are a popular model of human essential hypertension. To investigate the role of the tissue kallikrein-kinin system in cardiac remodeling, an adenovirus containing the human tissue kallikrein gene was injected intravenously into adult SHR and normotensive Wistar-Kyoto (WKY) rats. The blood pressure of WKY rats remained unchanged throughout the experiment. Alternatively, kallikrein gene transfer reduced blood pressure in SHR for the first 2 wk, but had no effect from 3 to 5 wk. Five weeks after kallikrein gene delivery, SHR showed significant reductions in LV-to-heart weight ratio, LV long axis, and cardiomyocyte size; however, these parameters were unaffected in WKY rats. Interestingly, cardiac collagen density was decreased in both SHR and WKY rats receiving the kallikrein gene. Kallikrein gene transfer also increased cardiac capillary density in SHR, but not in WKY rats. The morphological changes after kallikrein gene transfer were associated with decreases in JNK activation as well as transforming growth factor (TGF)-beta 1 and plasminogen activator inhibitor-1 levels in the heart. In addition, kallikrein gene delivery elevated LV nitric oxide and cGMP levels in both rat strains. These results indicate that kallikrein-kinin attenuates cardiac hypertrophy and fibrosis and enhances capillary growth in SHR through the suppression of JNK, TGF-beta 1, and plasminogen activator inhibitor-1 via the nitric oxide-cGMP pathway.     

Effect of pravastatin on development of left ventricular hypertrophy in spontaneously hypertensive rats

Endothelin (ET)-1 has been implicated in the development of cardiac hypertrophy. We investigated the effect of pravastatin on development of ventricular hypertrophy in spontaneously hypertensive rats (SHR) and whether the attenuated hypertrophic effect was via reduced ET-1 expression. Normolipidemic SHR were treated with one of the following therapies for 8 wk: vehicle, the nonselective ET receptor antagonists bosentan, pravastatin, mevalonate, hydralazine, or combination of pravastatin + mevalonate from the age of 8 wk at the very early stage of cardiac hypertrophy. Treatment with bosentan and pravastatin significantly decreased left ventricular mass index for body weight and cardiomyocyte sizes isolated by enzymatic dissociation. The myocardial ET-1 levels and preproET-1 mRNA assessed using real-time quantitative RT-PCR were significantly higher (both P < 0.001) in the SHR compared with Wistar-Kyoto rats. The increased tissue ET-1 levels can be inhibited after pravastatin administration. Immunohistochemical analysis confirmed the changes of ET-1. Left ventricular mass index for body weight correlated positively with tissue ET-1 levels (P = 0.0004). A dissociation between the effects of blood pressure and cardiac structure was noted, because pravastatin and hydralazine reduced arterial pressure similarly. Pravastatin-induced effects were reversed by the addition of mevalonate. In conclusion, these results suggest a crucial role of cardiac endothelin system in the early development of ventricular hypertrophy in the SHR. Pravastatin is endowed with cardiac antihypertropic properties that are independent of its hemodynamic and hypolipidemic effects and appear to be related to their capacity to decrease cardiac ET-1 levels, which is linked to mevalonate metabolism.     

Changes in hepatic protein expression in spontaneously hypertensive rats suggest early stages of non-alcoholic fatty liver disease

Hypertension is a systemic disorder affecting numerous physiological processes throughout the body. As non-alcoholic fatty liver disorder (NAFLD) is a common comorbidity of hypertension in humans, we hypothesized that molecular hepatic physiology would be altered in a model of genetic hypertension. Despite the broad use of the spontaneously hypertensive rat (SHR) model, little is known regarding how hypertension influences hepatic function under basal conditions. In order to determine whether hypertension induces changes in the hepatic protein expression suggestive of early stages of NAFLD, we compared the whole tissue proteome of livers from SHR and Wistar Kyoto (WKY) 16 week old rats using 2DGE and MALDI-TOF MS. Fifteen proteins were identified that display different levels of expression between the SHR and WKY livers: 50% of proteins have mitochondrial or anti-oxidant functions while 20% are involved in lipid metabolism. Quininoid dihydropterin reductase, sulfite oxidase, and glutathione-S-transferase mu 1 were all identified as either undergoing a difference in post-translation modification or a difference in protein abundance in SHR compared to WKY livers. As oxidative stress is a well described component of both NAFLD and hypertension in SHR, the identification of novel changes in protein expression provides possible mechanisms connecting these two pathologies in humans.     

Effect of hypertension on the development of diabetic cardiomyopathy

The effect of hypertension on the progression of diabetic cardiomyopathy was examined by attempting to induce a similar level of diabetes in both spontaneously hypertensive rats (SHR) and Wistar rats. Streptozotocin (STZ) was injected into SHR (45 mg/kg) and Wistar rats (55 mg/kg) before (eight weeks of age) and after (twelve weeks of age) the development of hypertension in the SHR. For both groups of animals, induction of diabetes resulted in depressed weight gain, increased food and fluid consumption, hypoinsulinemia, hyperglycemia, and hypertriglyceridemia. For the rats injected at eight weeks of age, an oral glucose tolerance test (OGTT) demonstrated that although the SHR were significantly less diabetic than Wistar rats, the degree of cardiac dysfunction was equivalent in both strains. These results suggest that hypertension was interacting with the diabetic condition to impair cardiac performance. Injecting SHR at twelve weeks of age increased the severity of diabetes but interestingly did not depress heart function compared with the non-diabetic SHR group. Injecting Wistar rats at this age also increased the severity of diabetes, but unlike the SHR diabetic animals, these rats still had impaired cardiac performance. These results suggest that hypertension exacerbates the cardiac dysfunction seen during diabetes, especially when SHR rats are injected with STZ prior to the elevation of blood pressure. Moreover, in the SHR, the development of LV hypertrophy at the time of STZ injection may have compensated for the damaging effects of diabetes on the myocardium, thereby enabling the heart to perform normally.     

Functional and structural pattern of arterial responses in hereditary hypertriglyceridemic and spontaneously hypertensive rats in early stage of experimental hypertension

It has been shown that endothelium-derived nitric oxide (NO) plays an important role in regulation of vascular tone in the prenatal and early postnatal period. The aim of this paper was to determine the reactivity and accompanying structural changes in thoracic aorta from 4-week-old spontaneously hypertensive rats (SHR) and rats with hereditary hypertriglyceridemia (hHTG) in comparison with age-matched normotensive controls. For functional studies thoracic aorta was excised, cut into rings and mounted in organ baths for measurement of isometric contractile force. For morphological studies cardiovascular system of rats was perfused with glutaraldehyde fixative (at 100 mm Hg) via cannula placed in the left ventricle. Morphological changes of thoracic aorta were measured using light microscopy. Systolic blood pressure (SBP) in SHR (98+/-1 mm Hg) did not significantly differ from that of age-matched control rats (95+/-4 mm Hg), but was slightly increased in hHTG rats (110+/-2 mm Hg, P<0.05). Heart weight/body weight ratio was higher in SHR and hHTG rats than in control group indicating the hypertrophy of the heart in both models of hypertension. Endothelium-dependent relaxation of aorta induced by acetylcholine was preserved in all groups and did not differ from that in control normotensive rats. The maximal isometric contraction of thoracic aorta to noradrenaline (NA) was reduced in hypertensive groups and the concentration-response curves to NA were shifted to the right indicating increased sensitivity of smooth muscle to NA. The values of wall thickness and cross sectional area as well as inner diameter of thoracic aorta in SHR and hHTG rats were significantly decreased in comparison to control groups. Endothelial dysfunction seems to be absent in all young rats before development of hypertension. In conclusion, our observations indicate that in early stage of experimental hypertension NO-dependent relaxation is preserved so that putative impairment of this function provides no significant pathogenic contribution to the onset of hypertension in these two experimental models.     

Hypertension-induced remodeling of cardiac excitation-contraction coupling in ventricular myocytes occurs prior to hypertrophy development

Hypertension is a major risk factor for developing cardiac hypertrophy and heart failure. Previous studies show that hypertrophied and failing hearts display alterations in excitation-contraction (E-C) coupling. However, it is unclear whether remodeling of the E-C coupling system occurs before or after heart disease development. We hypothesized that hypertension might cause changes in the E-C coupling system that, in turn, induce hypertrophy. Here we tested this hypothesis by utilizing the progressive development of hypertensive heart disease in the spontaneously hypertensive rat (SHR) to identify a window period when SHR had just developed hypertension but had not yet developed hypertrophy. We found the following major changes in cardiac E-C coupling during this window period. 1) Using echocardiography and hemodynamics measurements, we found a decrease of left ventricular ejection fraction and cardiac output after the onset of hypertension. 2) Studies in isolated ventricular myocytes showed that myocardial contraction was also enhanced at the same time. 3) The action potential became prolonged. 4) The E-C coupling gain was increased. 5) The systolic Ca(2+) transient was augmented. These data show that profound changes in E-C coupling already occur at the onset of hypertension and precede hypertrophy development. Prolonged action potential and increased E-C coupling gain synergistically increase the Ca(2+) transient. Functionally, augmented Ca(2+) transient causes enhancement of myocardial contraction that can partially compensate for the greater workload to maintain cardiac output. The increased Ca(2+) signaling cascade as a molecular mechanism linking hypertension to cardiac hypertrophy development is also discussed.     

Specificity of the hemodynamic indices’ shift in SHR line rats at different age

Specificities of the changes in the systemic hemodynamics indices in the spontaneously hypertensive line SHR rats have been studied in comparison with the normotensive line WKY rats. It was demonstrated that an increase in blood pressure observed in the young hypertensive male rats, which have completed puberty (8 weeks old), is associated with the development of the hyperkinetic type arterial hypertension, which is characterized by increased cardiac minute output. It has been shown that SHR line male rats reveal the establishment of stable arterial hypertension due to a significant increase in the total peripheral resistance with the simultaneous recovery of the cardiac minute output by the 25th week of life. SHR line rats at the age of 15 weeks may be regarded as being in the period of transition from the hyperkinetic type arterial hypertension to stable arterial hypertension.     

The relationship between altered blood vessel structure, hypertension, and the sympathetic nervous system

The relationship between sympathetic innervation and arterial medial development has been examined in normotensive, hypertensive, and diabetic rats. Using the jejunal artery as a model, the number of nerve fibres innervating the artery as determined from fluorescent preparations, and the medial thickness and lumen diameter as measured from resin embedded specimens were correlated from animals prepared in various ways. The rats used were normal Sprague-Dawley (SD), SD with induced hypertension, SD with diabetes induced with streptozotocin, SD sympathectomized with 6-hydroxydopamine, spontaneously hypertensive rats (SHR), SHR treated with capsaicin to prevent hypertension development, Wistar Kyoto rats (WKY), and WKY treated with capsaicin. Examination of the jejunal arteries from these rats at 12 weeks of age following normal development, or 8 weeks of hypertension development, or 8 and 12 weeks of diabetes, showed that increased innervation occurred in the SHR under all conditions, and in the diabetic rats after 8 weeks of diabetes. Medial hypertrophy occurred in the SHR and in the SD hypertensive only. It is concluded that the special relationship which exists between the sympathetic innervation and arterial media in the SHR does not occur during hypertension development in the SD rat, nor is it necessary for normal medial development in the SD rat. The sympathetic innervation does appear to have a trophic influence on vascular smooth muscle of diabetic rats, at least in the early stages of the disease.     

Hyper-phosphorylation of alpha-enolase in hypertrophied left ventricle of spontaneously hypertensive rat

Cardiac hypertrophy is one of the main target organ damages of essential hypertension and predicts a poor prognosis of the disease. The molecules involved in this event, especially their posttranslational modifications, remain largely unknown to date. With a combination of phosphoprotein column enrichment and two-dimensional gel electrophoresis separation, here we compared the profiling of enriched phosphoproteins from the left ventricle (LV) of spontaneously hypertensive rats (SHR) to that of age-matched Wistar Kyoto rats. As a result, 19 differential proteins were found in the hypertrophied LV of SHR. Among them, we focused on a glycolysis enzyme α-enolase, of which the hyper-phosphorylation was shown in the hypertrophied LV but not in non-hypertrophied atrium and right ventricle of SHR. Furthermore, the α-enolase hyper-phosphorylation was accompanied by decreased enzymatic activity. The further investigation based on these results would provide new clues to understand the pathological process of cardiac hypertrophy in SHR.     

Decreased cardiac mitochondrial NADP+-isocitrate dehydrogenase activity and expression: a marker of oxidative stress in hypertrophy development

Mitochondrial dysfunction subsequent to increased oxidative stress and alterations in energy metabolism is considered to play a role in the development of cardiac hypertrophy and its progression to failure, although the sequence of events remains to be elucidated. This study aimed at characterizing the impact of hypertrophy development on the activity and expression of mitochondrial NADP+-isocitrate dehydrogenase (mNADP+-ICDH), a metabolic enzyme that controls redox and energy status. We expanded on our previous finding of its inactivation through posttranslational modification by the lipid peroxidation product 4-hydroxynonenal (HNE) in 7-wk-old spontaneously hypertensive rat (SHR) hearts before hypertrophy development (Benderdour et al. J Biol Chem 278: 45154-45159, 2003). In this study, we used 7-, 15-, and 30-wk-old SHR and Sprague-Dawley (SD) rats with abdominal aortic coarctation. Compared with age-matched control Wistar-Kyoto (WKY) rats, SHR hearts showed a significant 25% decrease of mNADP+-ICDH activity, which preceded in time 1) the decline in its protein and mRNA expression levels (between 10% and 35%) and 2) the increase in hypertrophy markers. The chronic and persistent loss of mNADP+-ICDH activity in SHR was associated with enhanced tissue accumulation of HNE-mNADP+-ICDH and total HNE-protein adducts at all ages and contrasted with the profile of changes in the activity of other mitochondrial enzymes involved in antioxidant or energy metabolism. Two-way ANOVA of the data also revealed a significant effect of age on most parameters measured in SHR and WKY hearts. The mNADP+-ICDH activity, protein, and mRNA expression were reduced between 25% and 35% in coarctated SD rats and were normalized by treatment of SHR or coarctated SD rats with renin-angiotensin system inhibitors, which prevented or attenuated hypertrophy. Altogether, our data show that cardiac mNADP+-ICDH activity and expression are differentially and sequentially affected in hypertrophy development and, to a lesser extent, with aging. Decreased cardiac mNADP+-ICDH activity, which is attributed at least in part to HNE adduct formation, appears to be a relevant early and persistent marker of mitochondrial oxidative stress-related alterations in hypertrophy development. Potentially, this could also contribute to the aetiology of cardiomyopathy.     

Comparative changes in the blood-brain barrier and cerebral infarction of SHR and WKY rats

Hypertension is involved in the exacerbation of stroke. It is unclear how blood-brain barrier (BBB) tight-junction (TJ) and ion transporter proteins critical for maintaining brain homeostasis contribute to cerebral infarction during hypertension development. In the present study, we investigated cerebral infarct volume following permanent 4-h middle cerebral artery occlusion (MCAO) and characterized the expression of BBB TJ and ion transporter proteins in brain microvessels of spontaneously hypertensive rats (SHR) compared with age-matched Wistar-Kyoto (WKY) rats at 5 wk (prehypertension), 10 wk (early-stage hypertension), and 15 wk (later-stage hypertension) of age. Hypertensive SHR show increased infarct volume following MCAO compared with WKY control rats. BBB TJ and ion transporter proteins, known to contribute to edema and fluid volume changes in the brain, show differential protein expression patterns during hypertension development. Western blot analysis of TJ protein zonula occludens-2 (ZO-2) showed decreased expression, while ion transporter, Na(+)/H(+) exchanger 1 (NHE-1), was markedly increased in hypertensive SHR. Expression of TJ proteins ZO-1, occludin, actin, claudin-5, and Na(+)-K(+)-2Cl(-) cotransporter remain unaffected in SHR compared with control. Selective inhibition of NHE-1 using dimethylamiloride significantly attenuated ischemia-induced infarct volume in hypertensive SHR following MCAO, suggesting a novel role for NHE-1 in the brain in the regulation of ischemia-induced infarct volume in SHR.     

Exercise Training Attenuates Hypertension and Cardiac Hypertrophy by Modulating Neurotransmitters and Cytokines in Hypothalamic Paraventricular Nucleus

Aims

Regular exercise as an effective non-pharmacological antihypertensive therapy is beneficial for prevention and control of hypertension, but the central mechanisms are unclear. In this study, we hypothesized that chronic exercise training (ExT) delays the progression of hypertension and attenuates cardiac hypertrophy by up-regulating anti-inflammatory cytokines, reducing pro-inflammatory cytokines (PICs) and restoring the neurotransmitters balance in the hypothalamic paraventricular nucleus (PVN) in young spontaneously hypertensive rats (SHR). In addition, we also investigated the involvement of nuclear factor-κB (NF-κB) p65 and NAD(P)H oxidase in exercise-induced effects.

Methods and results

Moderate-intensity ExT was administrated to young normotensive Wistar-Kyoto (WKY) and SHR rats for 16 weeks. SHR rats had a significant increase in mean arterial pressure and cardiac hypertrophy. SHR rats also had higher levels of glutamate, norepinephrine (NE), phosphorylated IKKβ, NF-κB p65 activity, NAD(P)H oxidase subunit gp91^phox, PICs and the monocyte chemokine protein-1 (MCP-1), and lower levels of gamma-aminobutyric acid (GABA) and interleukin-10 (IL-10) in the PVN. These SHR rats also exhibited higher renal sympathetic nerve activity (RSNA), and higher plasma levels of PICs, and lower plasma IL-10. However, ExT ameliorates all these changes in SHR rats.

Conclusion

These findings suggest that there are the imbalances between excitatory and inhibitory neurotransmitters and between pro- and anti-inflammatory cytokines in the PVN of SHR rats, which at least partly contributing to sympathoexcitation, hypertension and cardiac hypertrophy; chronic exercise training attenuates hypertension and cardiac hypertrophy by restoring the balances between excitatory and inhibitory neurotransmitters and between pro- and anti-inflammatory cytokines in the PVN; NF-κB and oxidative stress in the PVN may be involved in these exercise-induced effects.     

Effect of swimming training on cardiac function and myosin ATPase activity in SHR

Male spontaneously hypertensive rats (SHR) and Wistar-Kyoto normotensive rats (WKY) were subjected to swimming training 6 times/wk, commencing at 4 wk of age, to determine whether this type of endurance exercise might alter contractile proteins and cardiac function in young adult SHR. The total duration of exercise was 190 h. Myofibrillar adenosinetriphosphatase (ATPase) activity was assayed at various free [Ca2+] ranging from 10(-7) to 10(-5) M. Ca2+-stimulated ATPase activity of actomyosin and purified myosin was determined at various Ca2+ concentrations both in the low and high ionic strength buffers. Actin-activated myosin ATPase activity of purified myosin was assayed at several concentrations of actin purified from rabbit skeletal muscle. Under all these conditions the contractile protein ATPase activity was comparable between trained and untrained WKY and SHR. Analysis of myosin isoenzymes on pyrophosphate gels showed a single band corresponding to V1 isoenzyme, and there were no differences between swimming-trained and nontrained WKY and SHR. Ventricular performance was assessed by measuring cardiac output and stroke volume after rapid intravenous volume overloading. Both cardiac index and stroke index were comparable in nontrained WKY and SHR but were significantly increased in the trained groups compared with their respective nontrained controls. These results suggest that myosin ATPase activity and distribution of myosin isoenzymes are not altered in the moderately hypertrophied left ventricle whether the hypertrophy is due to genetic hypertension (SHR) or to exercise training (trained WKY). Moreover, the data indicate that SHR, despite the persistence of a pressure overload, undergo similar increases in left ventricular mass and peak cardiac index after training, as do normotensive WKY.     

运动性和高血压性心肌肥大重塑时心肌初级和次级应答基因表达的差异

我们前期研究表明运动性和高血压性心肌肥大细胞表型变化在结构、功能和代谢方面均表现不同,但两者基因表达的不同特征尚不清楚。本实验采用Ｎｏｒｔｈｅｒｎ分子杂交方法对游泳运动１２周大鼠和自发性高血压大鼠（ＳＨＲ）肥大心脏心肌初级和次级应答基因表达进行比较研究。结果表明,游泳大鼠心系数比对照大鼠提高２６％（Ｐ〈０．０１）,心肌ｃ－ｆｏｓ和心房钠尿肽（ＡＮＦ）基因表达在最后一次运动后即刻明显增强,在运动后２     

Smooth muscle function of the portal vein in spontaneously hypertensive rats

Increased contractility and adrenoreactivity of the portal vein smooth muscles were revealed in spontaneously hypertensive rats (SHR) only at the early stage of the disease. In stable hypertension the changes were milder both at the early and chronic stages. Portal vein smooth muscles were capable of contracting in low-calcium medium, which suggests a membrane defect in the smooth muscles of animals with arterial hypertension.     

四种不同高血压大鼠模型形成过程中血清抗AT1A受体自身抗体的检测

本实验采用不同的方法复制两肾-夹（two-kidney one-cliprenal hypertensive,2K1C）、神经性、DOCA-盐高血压和自发性高血压大鼠模型,观察AT1A受体自身抗体（AT1A-receptorautoantibodies,AT1A-AAs）在不同高血压发病的变化规律,同时对自身抗体生物活性进行分析。实验结果表明,在高血压发病过程中AT1A-AAs的阳性率和滴度均明显增加,在四种模型中,自发性高血压组最明显,2K1C和神经性组次之。AT1A-AAs的生物活性显示,可增加培养的新生鼠心肌细胞跳动频率和血管收缩张力。结果提示,自身免疫机制参与了高血压的形成,AT1A-AAs可能与心肌肥厚有关。     

Casein kinase 2 inactivation by Mg2+, Mn2+ and Co2+ ions

In order to elucidate the relationship between hypertension and hypertrophy in the production of heat shock proteins, we studied the induction of the HSP72 synthesis by the heart and gracilis muscles of normo (WKY) and hypertensive (SHR) rats subjected to hyperthermia (42°C±0.5 for 15 min). Two age groups were investigated in each strain: young (2 months, with developing cardiac hypertrophy) and old (18 months, with fully developed chronic cardiac hypertrophy). The gracilis muscle never developed hypertrophy, independently of hypertension or aging. 72 kDa inducible protein was determined by Western blot analysis using a specific monoclonal antibody. We also used a commercial standard, loaded on each blot, to quantitate densitometrically the signal.The heart of young SHR responds to heat shock more than their normotensive age-matched control (298.8±24.7% vs 88.3 ±8.5%, p<0.001). This response is not maintained during aging as we did not find any significant difference between normo-and hypertensive old rats after exposure to hyperthermia (43.6±5.3% vs 65.3±10.4%).Unlike the heart, the gracilis muscle shows a basal spontaneous HSP72 synthesis in both the SHR (71.4±10.8%) and WKY (40.6±11.7%) animals. There was a significant increase in HSP72 synthesis in the gracilis muscle of young SHR with respect to their control (186.2±18.7% vs 115.8±9.9%, p<0.02) which was maintained also during aging (171.9±17.3% vs 95.2±10.5%, p<0.01).In conclusion, these data show that hypertension results in an increased synthesis of HSP72 both in cardiac and gracilis muscle in response to heat shock. This abnormal response is attenuated by aging in the heart but not in the gracilis muscle. Thus, the abnormality seems to be independent from hypertrophy and linked to genetic determination of the disease.     

Increased expression of IL-6 and LIF in the hypertrophied left ventricle of TGR(mRen2)27 and SHR rats

Cytokines from the interleukin-6 (IL-6) family have been reported to play an important synergistic role with angiotensin II in the development of pathological cardiac hypertrophy. Whether their expression pattern changes in vivo, in an angiotensin II-dependent hypertrophied myocardium has not been reported. In this study, we addressed that issue using two animal models of angiotensin II-dependent cardiac hypertrophy. Heterozygous transgenic TGR(mRen2)27 (TGR) with an overactive cardiac renin angiotensin system and the closely related spontaneously hypertensive rats (SHR) were compared to their respective control rats. The mRNA levels of IL-6, leukemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF) and cardiotrophin-1 (CT-1) as well as their receptor subunits, glycoprotein 130 (gp130), IL-6 receptor (IL-6R), LIFR, and CNTFR, were measured by semi-quantitative RT-PCR. The protein levels of IL-6, LIF and CT-1 were investigated by western blot. TGR and SHR both displayed significant over expression of mRNA and protein levels for IL-6 and LIF. In TGR, the increased level of LIF was accompanied by a decrease in mRNA levels for LIFR and CNTFR. In SHR, a higher level of mRNA IL-6R was observed. By contrast, the mRNA and protein levels for CT-1 and the mRNA level for gp130 did not vary in these two models. These findings suggest that IL-6 and LIF, but not CT-1, contribute to angiotensin II-dependent left ventricular hypertrophy in the two hypertensive rat models, TGR(mRen2)27 and SHR. (Mol Cell Biochem 269: 95–101, 2005)