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At least 865 records · Page 48Linked to original sources
PubMed1999

Cardiac endothelin and big endothelin in right-heart hypertrophy due to monocrotaline-induced pulmonary hypertension in rat.

OBJECTIVE: Recent observations suggest the existence of a myocardial endothelin (ET) system and its possible involvement in left-ventricular myocardial hypertrophy and failure. However, nothing is known about the role of myocardial ET in right-ventricular hypertrophy. METHODS: Rats (80-100 g) were given an intraperitoneal injection of saline (controls) or monocrotaline (50 mg/kg) resulting in pulmonary hypertension-induced myocardial hypertrophy (n = 11 in both groups). After 10 weeks, the animals were sacrificed and hearts perfused in vitro to determine levels of big ET-1 and ET-1 in coronary effluent, interstitial fluid and ventricular tissue homogenates; plasma levels were also determined. RESULTS: In monocrotaline-treated animals, weights of right ventricles were 1.5 and of right atria 1.8-fold higher than in controls (p < 0.05), indicating substantial right-ventricular hypertrophy as also evident from greatly increased myocardial production of atrial natriuretic peptide. Left-ventricular weights were not different. Release of big ET-1 in coronary effluent, and of ET-1 in coronary effluent and interstitial transudate were similar in control and hypertrophic hearts (p > 0.05). Disruption of endothelium with collagenase reduced release of both peptides close to zero, indicating endothelial (not myocardial) origin of the peptides. Levels of big ET-1 and ET-1 were similar in left ventricles of both experimental groups, but lower in right ventricles of hypertrophic than control hearts (p < 0.05), reflecting increased tissue mass rather than reduced peptide production. On the other hand, plasma levels of both peptides and of ANP were twofold and levels of angiotensin II 1.3-fold higher in rats with right-heart hypertrophy than in controls (p < 0.05 in each case). CONCLUSION: These data do not support a role for local cardiac ET-1 and/or big ET-1 in right-ventricular hypertrophy, but point to blood-borne endothelins as possible mediators.

Analysis of Variance↗
PubMed2000

Effects of carnitine palmitoyltransferase I inhibitors on hepatic hypertrophy.

We investigated the effect of two types of carnitine palmitoyltransferase I inhibitors, ethyl 2-(6-(4-chlorophenoxy)hexyl)oxirane-2-carboxylate (etomoxir) and (R)-3-carboxy-N,N, N-trimethyl-2-¿[hydroxy(tetradecyloxy)phosphinyl]oxy¿-1-propana minium hydroxide (SDZ CPI 975), on cardiac and hepatic hypertrophy in ddY mice. One-week administration of etomoxir caused cardiac and hepatic hypertrophy, 19% and 22% as a ratio to body weight, respectively. Although 4-week administration of etomoxir caused hepatic hypertrophy, there was no significant change in liver triglyceride content in the first or second week. In cultured HepG(2) cells, etomoxir treatment (1 week) did not cause triglyceride to accumulate. One-week administration of SDZ CPI 975 caused neither cardiac nor hepatic hypertrophy. In vitro, neither drug had selectivity for carnitine palmitoyltransferase I isozymes. These findings suggest that the hepatic hypertrophy following 1- or 2-week treatment with etomoxir is caused by mechanisms different from those responsible for triglyceride accumulation, and that inhibition of carnitine palmitoyltransferase I may not necessarily induce hepatic hypertrophy.

Acyl Coenzyme A↗
PubMed1999

Electrocardiographic left ventricular hypertrophy by five criteria among civil servants in Benin City, Nigeria: prevalence and correlates.

Although increasing hypertension rates have been reported in several African populations, little is known about the frequency of resulting hypertensive complications in these populations. We recorded the electrocardiograms of 482 male and 284 female civil servants in Benin City, Nigeria. Five different criteria were used to detect the presence of electrocardiographic left ventricular hypertrophy. Associations between electrocardiographic left ventricular hypertrophy and demographic, anthropometric and blood pressure characteristics were assessed. The prevalence of electrocardiographic left ventricular hypertrophy ranged from 3 to 29% in the total population, depending on the criteria used, with four of the five criteria resulting in prevalence estimates of less than 10%. The prevalence of electrocardiographic left ventricular hypertrophy was significantly greater among those with hypertension (19% of the total population), ranging from 11 to 49%. The prevalence of electrocardiographic left ventricular hypertrophy increased with blood pressure level in both normotensives and hypertensives. Among hypertensives with systolic blood pressure > or =180 mm Hg or diastolic blood pressure > or =110 mm Hg, the prevalence exceeded 50% by four of the five criteria. We conclude that left ventricular hypertrophy may be affecting many hypertensives in this Nigerian population, potentially resulting in a substantial future burden of cardiovascular disease and death.

Adult↗
PubMed2005

[Neurogenic muscle hypertrophy: imaging features in three cases and review of the literature].

OBJECTIVE: To review the literature on well-documented cases of neurogenic muscle hypertrophy in order to define significant features of this disease. PATIENTS AND METHODS: The PUBMED and SCIENCE DIRECT web-sites were used to conduct an inventory of all reported cases of this disease. We entered the key-words "hypertrophy", "muscle" and "neurogenic", and found 48 articles, describing 129 cases. Our criteria of inclusion included hypertrophy of one or several muscles of a lower limb, previous realization of at least one imaging study (CT or MRI) and electromyography of lower limbs; criterion of exclusion was hypertrophy related to hereditary or acquired polyneuropathies. Twenty-five cases were retained for investigation along with 3 recent cases observed in our department. RESULTS: Results show that neurogenic muscle hypertrophy is usually presents with painful enlargement of a calf in a male, aged 32 to 60 years, with previous history of low back pain and sciatica, 68% of the time due to disk herniation or lumbar stenosis. Other clinical findings may include radiation therapy or trauma. CONCLUSION: The symptoms of neurogenic muscle hypertrophy may lead to MRI examination before electromyography. This disease should be included in the differential diagnosis.

Adult↗
PubMed1994

[Left ventricular hypertrophy of hypertensive origin: classical concepts and recent data].

Left ventricular hypertrophy occurs in numerous hypertensive patients. It can be diagnosed by using echocardiography, whose sensibility (93%) and sensitivity (95%) are both excellent, provided the quality of the recordings is good enough (80%). Most often, left ventricular hypertrophy is a concentric one (relative wall thickness greater than 0.45). The determinants of hypertensive left ventricular hypertrophy are of mechanical and hormonal origin; Weber's and Brilla's recent findings suggest that the haemodynamic burden should be responsible for myocytes hypertrophy, whereas hormonal factors stimulate fibrosis proliferation. Although left ventricular hypertrophy is initially an adaptative process, it eventually results in numerous deleterious effects: arrhythmias, myocardial ischemia, left ventricular filling abnormalities. Left ventricular hypertrophy is now recognized as a powerful blood-pressure independent risk factor for cardio-vascular morbidity and mortality. Therefore, antihypertensive therapy must be aimed at reducing not only blood pressure but also left ventricular mass. Most of the published regression studies have however to be criticized from a methodologic standpoint.

Humans↗
PubMed1998

Insertion/deletion polymorphism in intron 16 of the ACE gene and left ventricular hypertrophy in patients with end-stage renal disease.

We studied the relationship between polymorphism in intron 16 of the angiotensin-converting enzyme (ACE) gene and left ventricular (LV) hypertrophy in uremic patients treated with hemodialysis therapy. The LV parameters were not different for age-, hematocrit-, and blood pressure-matched patients in DD, ID, and II genotype groups. The most important factor for LV hypertrophy was systolic blood pressure, which correlated with the posterior wall thickness (r=0.35; P=0.001) and LV mass index (LVMI; r=0.23; P=0.032). Among nonhypertensive patients, the frequency of interventricular septum (IVS) hypertrophy (>12 mm) and hypertrophy in LVMI (>145 g/m2) was significantly greater in patients with the DD genotype than in I allele-positive (+) patients. The odds rate for IVS hypertrophy was 5.04 (95% confidence interval, 1.15 to 24.8). These data suggest that the DD genotype of the ACE gene polymorphism is a contributory factor for the development of LV hypertrophy in patients with end-stage renal disease (ESRD).

Age Factors↗
PubMed2002

The antioxidant N-2-mercaptopropionyl glycine attenuates left ventricular hypertrophy in in vivo murine pressure-overload model.

OBJECTIVES: In order to identify the role of reactive oxygen species (ROS) in cardiac hypertrophy, we examined the effect of N-2-mercaptopropionyl glycine (MPG) on cardiac hypertrophy. BACKGROUND: Recent in vitro studies have suggested that ROS play an important role as a second messenger in cardiac hypertrophy. It was therefore thought to be of particular value to examine the relevance of studies using in vitro models for cardiac hypertrophy in an in vivo setting. METHODS: The transverse thoracic aorta in mice was constricted, and MPG (100 mg/kg) was infused intraperitoneally twice daily. The animals were assessed seven days after the operation for hemodynamic functions, oxidative stress and antioxidative enzyme activities. RESULTS: Banding of the transverse aorta in mice resulted in an increase in the ratio of heart weight to tibia length and the appearance of an endogenous atrial natriuretic factor messenger ribonucleic acid (mRNA) seven days postoperatively. Administration of MPG significantly attenuated the hypertrophic responses induced by pressure overload. Cardiac hypertrophy was accompanied by increases in heme oxygenase-1 mRNA expression and lipid peroxidation, which was eliminated by the treatment with MPG. Pressure overload led to increases in antioxidant enzyme activities, such as superoxide dismutase and glutathione peroxidase, but not catalase, activity. CONCLUSIONS: Our results indicated that oxidative stress was increased in our model and that it plays an important role in the development of cardiac hypertrophy.

Animals↗
PubMed1996

The renin-angiotensin system and vascular hypertrophy.

In addition to its vasoconstrictor and aldosterone-stimulating action, angiotensin II also drives cell growth and replication in the cardiovascular system, which may result in myocardial hypertrophy and hypertrophy or hyperplasia of conduit and resistance vessels in certain subjects. These actions are mediated through angiotensin II receptors (subtype AT1), which activate the G protein, phospholipase C, diacylglycerol and inositol trisphosphate pathway, to increase the expression of certain protooncogenes (c-fos, c-myc and c-jun) and growth factors (platelet-derived growth factor-A-chain, transforming growth factor-beta 1 and basic fibroblast growth factor). The cellular responses to angiotensin II in vascular smooth muscle have been shown in different hypertensive vessels to be either hypertrophy alone, hypertrophy and DNA synthesis without cell division (polyploidy) or DNA synthesis with cell division (hyperplasia). In genetic hypertension, the altered structure of small arteries is due to either cellular hyperplasia or remodeling, whereas in renovascular hypertension there is hypertrophy of vascular smooth muscle cells. Angiotensin II also increases synthesis of some matrix components, activates blood monocytes and is thrombogenic. Angiotensin-converting enzyme (ACE) inhibitors prevent or reverse vascular hypertrophy in animal models of hypertension; this seems to be a class effect, shared to some extent with calcium channel blocking agents. In human hypertension, ACE inhibitors reduce the increased media/lumen ratio of large and small arteries in hypertension and increase arterial compliance. These properties are also shared by losartan, the first of the new class of angiotensin II receptor (AT1) antagonists. The clinical implications of these findings need to be tested through rigorous and prospective clinical trials.

Angiotensin II↗
PubMedDate not supplied

Myocardial ultrasonic tissue characterization in patients with different types of left ventricular hypertrophy: a videodensitometric approach.

Although analysis of the radio frequency signal is the most accurate approach to myocardial tissue characterization, clinical diffusion has been limited because of the complex technology required. Much easier to perform, videodensitometric analysis could represent a valuable alternative. Previous works carried out on radio frequency data have shown that the absolute value of ultrasonic back scatter increases while its diastole-to-systole variation decreases in the hypertrophied myocardium. This study was aimed at clarifying whether alterations in characterization indexes of ultrasonic tissue can be detected by means of a videodensitometric approach, whether a specific type of left ventricular (LV) hypertrophy can be identified with this method, and finally what possible relationships exist between parameters of contractile function and tissue characterization indexes. Myocardial echo intensity (MEI), its cyclic variation (CV), and the dynamic relationship between myocardial signal and wall thickness variations during the cardiac cycle were assessed in 20 healthy subjects, 11 patients with essential hypertension and LV hypertrophy, 15 patients with hypertrophic cardiomyopathy, and 4 patients with primary amyloidosis. The CV was lower in the interventricular septum of patients with cardiac hypertrophy as a group, compared with that of control subjects (13.0% +/- 5.6% versus 18.8% +/- 5.5%, p < 0.001), but it was similar among patients with different types of hypertrophy. In control subjects, a significant inverse correlation was found between the progressive decrease of the myocardial signal and the parallel increase in wall thickness during systole; this correlation was lost in 60% of patients with hypertrophic cardiomyopathy and 50% of those with amyloidosis, but only in 9% of patients with essential hypertension (chi square analysis 12.68, p < 0.01). The CV was associated with systolic wall thickening (r = 0.53, p = 0.0001) and fractional shortening (r = 0.44, p = 0.0014). MEI and its CV per se cannot distinguish among different types of LV hypertrophy; however, the loss of an inverse relationship between the myocardial signal and wall thickness may suggest abnormal myocardial conditions in individual patients with the same disease or comparable wall thickness.

Adult↗
PubMed2002

Left ventricular diastolic function in physiologic and pathologic hypertrophy.

BACKGROUND: Patients with hypertensive heart disease and left ventricular hypertrophy demonstrate an impaired left ventricular diastolic filling pattern. The aim of this study was to find out whether physiologic left ventricular hypertrophy induced by endurance training causes disturbances in left ventricular systolic and diastolic filling. METHODS: We examined 49 athletes with left ventricular (LV) hypertrophy due to endurance training, 49 patients with LV hypertrophy due to arterial hypertension, and 26 untrained healthy control subjects by conventional echocardiography. Parameters of LV diastolic filling using pulse wave and color flow Doppler were also assessed. RESULTS: All three study groups showed normal fractional shortening and mid-wall fractional shortening. Conventional echocardiography revealed a higher LV muscle mass index in the two study groups compared with the controls (athletes, 99 +/- 10 g; hypertensive patients, 95 +/- 11 g: controls: 52 +/- 7 g; P < .01 for athletes and hypertensive patients). In patients with arterial hypertension, a diastolic dysfunction consisting of a delayed relaxation pattern with a decrease in maximal early velocity of diastolic filling (0.44 +/- 0.1 m/sec) and a compensatory increase of the maximal late velocity of diastolic filling (0.53 +/- 0.1 m/sec) was demonstrated. In athletes with physiologic LV hypertrophy, a normal LV diastolic filling pattern was documented. CONCLUSIONS: Doppler echocardiographic parameters of LV diastolic function can be of diagnostic importance for discrimination between pathologic and physiologic LV hypertrophy.

Adult↗
PubMed2001

Dendritic hypertrophy of Stach type VI neurons within experimentally altered ileum of pigs.

Myenteric neurons were investigated morphometrically to answer the question if type-specific somal hypertrophy of type VI neurons in mechanically stressed ileum of pigs, which was known from an earlier study, is correlated with an increased dendritic arborization, that is, with dendritic hypertrophy. Muscular hypertrophy was induced in the ileum of two juvenile pigs by narrowing the gut circumference (mechanical stenosis) and by reversing a loop of ileum which results in an antiperistaltic segment (functional stenosis), respectively. After a survival time of 6 weeks, wholemounts from the pre- and poststenotic ileal regions, from the antiperistaltic segment as well as from an age matched control animal, were silver impregnated. Dendritic parameters of Stach types IV and VI neurons were recorded using a computer-aided morphometric program and analysed statistically. Type IV neurons showed no change of dendritic parameters, neither within control nor within stenosed ileal segments. In contrast, the type VI neurons displayed increased dendritic parameters within zones of muscular hypertrophy such as total dendritic length, numbers of dendrites, of dendritic branching points and of dendritic endings. We suggest that type VI neurons may participate as descending nitrergic interneurons or motorneurons in the control of muscular function, thus, undergoing plastic changes in case of experimental muscular hypertrophy. Type IV neurons which are involved in the regulation of mucosal processes were not affected by muscular hypertrophy.

Animals↗
PubMed2002

Ventricular hypertrophy induced by mineralocorticoid treatment or aortic stenosis differentially regulates the expression of cardiac K+ channels in the rat.

Rats treated with DOCA salts and subjected to abdominal aortic stenosis display left ventricle hypertrophy associated with a decrease in cardiac I(to) current density and prolongation of the action potential duration. We investigated the molecular basis of these electrophysiological defects by analyzing the amount of mRNA corresponding to the genes encoding the a subunits of the left ventricle K+ channel at the steady state. The mRNAs corresponding to the a subunits of the K+ channel (Kv1.2, Kv1.4, Kv1.5, Kv2. 1, Kv4.2 and Kv4.3) were measured by quantitative RT-PCR using a specific Kv internal standard. In control rats, the Kvl.5 gene was only expressed at a low level, whereas the Kv4.2 and Kv4.3 genes were expressed at a high level. Regardless of the etiology of the hypertrophy, the amounts of Kv1.4 and Kv1.5 mRNAwere similar in treated, sham and control rats. The amounts of Kv1.2 and Kv2.1 mRNA were markedly lower in DOCA-salt treated rats (66%) than in sham-DOCA rats, but no effect was observed after stenosis. The very conservative Kv4.2 and Kv4.3 genes were found to be downregulated simultaneously in both type of hypertrophy. However, the steady-state amount of Kv4 mRNA was even lower in rats with DOCA-salt-induced hypertrophy than in those with stenosis-induced ventricular hypertrophy. Therefore, the decrease in I(to) density, consecutively to pressure- and volume-overload, is due to a large decrease in the amount of Kv4.2 and Kv4.3 mRNA. In addition, DOCA-salt treatment alters the amounts of Kv transcripts independently to cardiac hypertrophy, suggesting that the mineralocorticoid may be involved in Kv gene expression.

Animals↗
PubMed2000

Antihypertensive treatment modulates the association between the D/I ACE gene polymorphism and left ventricular hypertrophy: a meta-analysis.

This meta-analysis attempted to derive pooled estimates for the putative association between echocardiographic or electrocardiographic left ventricular hypertrophy and the deletion/insertion (D/I) polymorphism of the angiotensin-I converting enzyme. Case-control studies were combined, using the Mantel and Haenszel approach. Joint P-values for continuous variables were calculated by Stouffer's method. Continuous measurements of left ventricular mass, which were reported in different units, were expressed on a percentage scale using the within-study mean of the II genotype as the denominator. The computerised database used for this analysis, included 28 reports with an overall sample size of 6638 subjects. The prevalence of the D allele was significantly lower in Japanese (37.2%) than in Caucasians (56.2%). A funnel plot including 12 case-control studies (4094 subjects) suggested that no publication bias was present. Overall, left ventricular hypertrophy was not associated with the D allele. Compared with the II genotype, the excess risks of left ventricular hypertrophy associated with DD and DI genotypes were only 14% (95% CI: 0.92-1.42; P = 0.23) and 5% (95% CI: 0.87-1.28; P = 0.61), respectively. However, the sensitivity analysis showed that in untreated hypertensive patients the DD genotype, compared with II homozygozity, was associated with a 192% (P = 0.002) higher risk of left ventricular hypertrophy. If left ventricular mass was analysed as a continuous trait across 23 studies (5438 subjects), overall no association with the D/I polymorphism was present. However, if untreated hypertensive patients were analysed separately, echocardiographic left ventricular mass was on average 10.1% (95% CI: 4.8-15.5%; P = 0.001) higher in DDhomozygotes than in the II reference group. Thus, in untreated hypertensive patients, in case-control studies as well as association studies, the D allele behaved as a marker for left ventricular hypertrophy. These findings support the hypothesis that the enhanced ACE activity associated with the D allele may promote left ventricular hypertrophy if a pathophysiologic process causing this disorder, remains unopposed by treatment.

Alleles↗
PubMed2004

Impact of age on left ventricular hypertrophy regression during antihypertensive treatment with losartan or atenolol (the LIFE study).

To assess the influence of age on changes in left ventricular (LV) mass and geometry during antihypertensive treatment, we related age to clinical and echocardiographic findings before and after 4 years of antihypertensive treatment in a subset of 560 hypertensive patients without known concurrent disease in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study, which randomized patients to blinded losartan- or atenolol-based treatment. Patients >/=65 years (older group) included more women and patients with isolated systolic hypertension or albuminuria (all P<0.05). Compared to patients <65 years, older patients had higher pulse pressure, LV mass, and prevalence of concentric hypertrophy at baseline (78 vs 69 mmHg, 234 vs 224 g, and 28 vs 16%, respectively, all P<0.01), while the mean blood pressure did not differ. Over 4 years, reductions in LV mass and the mean blood pressure were similar in both groups, but older patients more often had residual hypertrophy (31 vs 15%, P<0.001) with a preponderance of eccentric geometry. In multivariate analysis of 4-year change in LV mass controlling for baseline mass, larger hypertrophy reduction was associated with losartan treatment, while age, gender, body mass index, and 4-year change in pulse pressure and albuminuria did not enter (Multiple R (2)=0.40, P<0.001). Thus, in up-to-80-year-old hypertensive patients with left ventricular hypertrophy, age did not significantly attenuate hypertrophy reduction during antihypertensive treatment, although residual hypertrophy was more prevalent in older patients as a consequence of higher initial LV mass.

Age Factors↗
PubMed2001

Targeted overexpression of ornithine decarboxylase enhances beta-adrenergic agonist-induced cardiac hypertrophy.

These studies were designed to determine the consequences of constitutive overexpression of ornithine decarboxylase (ODC) in the heart. Induction of ODC is known to occur in response to agents that induce cardiac hypertrophy. However, it is not known whether high ODC levels are sufficient for the development of a hypertrophic phenotype. Transgenic mice were generated with cardiac-specific expression of a stable ODC protein using the alpha-myosin heavy-chain promoter. Founder lines with >1000-fold overexpression of ODC in the heart were established, resulting in a 50-fold overaccumulation of putrescine, 4-fold elevation in spermidine, a slight increase in spermine and accumulation of large amounts of cadaverine compared with littermate controls. Despite these significant alterations in polyamines, myocardial hypertrophy, as measured by ratio of heart to body weight, did not develop, although atrial natriuretic factor RNA was slightly elevated in transgenic ventricles. However, stimulation of beta-adrenergic signalling by isoproterenol resulted in severe hypertrophy and even death in ODC-overexpressing mice without further altering polyamine levels, compared with only a mild hypertrophy in littermates. When beta1-adrenergic stimulation was blocked by simultaneous treatment with isoproterenol and the beta1 antagonist atenolol, a significant, although reduced, hypertrophy was still present in the hearts of transgenic mice, suggesting that both beta1 and beta2 adrenergic receptors contribute to the hypertrophic phenotype. Therefore these mice provide a model to study the in vivo co-operativity between high ODC activity and activation of other pathways leading to hypertrophy in the heart.

Adrenergic beta-Agonists↗
PubMed1986

Changes in skeletal-muscle myosin isoenzymes with hypertrophy and exercise.

The patterns of myosin isoenzymes in fast- and slow-twitch muscles of the rat hindlimb were studied, by pyrophosphate/polyacrylamide-gel electrophoresis, with hypertrophy (induced by synergist removal) and with spontaneous running exercise of 4 and 11 weeks duration. At 11 weeks, changes with hypertrophy in the slow-twitch soleus, composed of greater than 95% SM2 (slow myosin 2) in normal muscles, were minor, and consisted of an increase in the SM1 and SM1', and a loss of intermediate myosin (IM), an isoenzyme characteristic of Type IIa fibres [Fitzsimons & Hoh (1983) J. Physiol. (London) 343, 539-550]. The changes were dramatic, however, in the fast-twitch plantaris muscle. There was a 3-fold increase in the proportion of SM. In addition, IM became the predominant isoenzyme in the profile of hypertrophied plantaris by 4 weeks. These increases were balanced by decreases in the proportion of FM2 (fast myosin 2), with FM1 completely absent from the profile at 11 weeks. The changes in the plantaris with exercise were similar in direction but not as extensive as those with hypertrophy, and FM1 remained present at control levels throughout the study. When hypertrophy and exercise were combined, the increase in slow myosin was equal to the sum of the increases with each treatment alone. Changes at 4 weeks were intermediate between those of control and 11-week muscles. Peptide mapping of individual myosin isoenzymes showed that the heavy chains of IM were different from either fast or slow heavy chains. Furthermore, IM was found to be composed of a mixture of fast and slow light chains. These changes suggest that a transformation of myosin from fast to slow isoforms was in progress in the plantaris in response to hypertrophy, via a Type-IIa-myosin (IM) intermediate stage, a phenomenon similar to that occurring in chronically stimulated fast muscles during fast-to-slow transformation [Brown, Salmons & Whalen (1983) J. Biol. Chem. 258, 14686-14692].

Adenosine Triphosphatases↗
PubMed1998

Angiotensin II-mediated expression of p27Kip1 and induction of cellular hypertrophy in renal tubular cells depend on the generation of oxygen radicals.

BACKGROUND: Angiotensin II (Ang II) induces hypertrophy of cultured proximal tubular cells. We have previously demonstrated that this Ang II-mediated hypertrophy occurs in the G1-phase of the cell cycle and depends on the induction of p27Kip1, an inhibitor of G1-phase cyclin/cyclin-dependent kinase complexes. The present study was undertaken to investigate whether Ang II may stimulate superoxide anions (O2.) formation in cultured LLC-PK1 and cultured mouse proximal tubule (MCT) cells, and to gain further insight into a potential relationship between O2. and cell cycle regulation. METHODS: Reactive oxygen species were measured with the lucigenin method in intact cells. The effects of various inhibitors were tested on Ang II-induced O2. production. Cells were transiently transfected with phosphorothioate-modified rat p22phox antisense oligonucleotides to investigate the potential role of NAD(P)H oxidase. Expression of p22phox mRNA after Ang II-treatment was detected with Northern blots. Incorporation of [3H]leucine into de novo synthesized proteins was used as a parameter of cell hypertrophy. Expression of p27Kip1 was evaluated in cell lysates by Western blotting. RESULTS: Ang II stimulated the accumulation of O2. in tubular cells; however, an addition of two different antioxidants completely abolished measurable O2. This effect was transduced by angiotensin receptor type-1 (AT1) and was inhibited by a flavoprotein inhibitor (DIP) or p22phox antisense oligonucleotides, indicating the involvement of membrane NAD(P)H oxidase. Ang II-stimulated de novo protein synthesis was attenuated by DIP, antioxidants, and p22phox antisense oligonucleotides. The Ang II-induced expression of p27Kip1 protein and cellular hypertrophy were reduced by similar treatments. Generation of O2. by xanthine supplementation also stimulated p27Kip1 expression and induced hypertrophy in LLC-PK1 cells. CONCLUSIONS: This study provides the first evidence, to our knowledge, that Ang II induces O2. in cultured tubular cells. Ang II-mediated activation of membrane bound NAD(P)H oxidase, probably by an increase in p22phox transcripts, is likely responsible for this induction. Generation of O2. subsequently induces p27Kip1 expression and stimulates hypertrophy, suggesting a novel mechanism of how Ang II can modulate cell cycle regulation.

Angiotensin II↗
PubMed1998

Mesangial cell hypertrophy induced by NH4Cl: role of depressed activities of cathepsins due to elevated lysosomal pH.

Enhanced ammoniagenesis is currently thought to play an important role in renal hypertrophy and subsequent tubulointerstitial fibrosis. Under certain conditions glomeruli also may be affected by ammonia toxicity. Exposure of glomeruli to augmented ammonia levels may occur: (i) in advanced liver diseases due to elevated blood ammonia concentrations; (ii) in conditions of enhanced tubular ammoniagenesis following cortical "trapping;" and (iii) due to increased ammonia formation in the glomeruli in the presence of impaired renal function. To elucidate the potential role of ammonia in glomerular injury, we investigated the effect of NH4Cl on protein turnover as well as on activities of various cathepsins in cultured rat mesangial cells. The results show that NH4Cl (20 mM) induced cell hypertrophy as defined by an increase in both cell protein content and cell volume (+38% and +10.1%, respectively, after 48 hr). This hypertrophy was associated with suppression of the activities of cathepsins B and L + B (-56.8% and -51.3% after 48 hr) and reduction of protein degradation rate (-61% after 48 hr), but without enhanced protein synthesis. Inhibition of Na+/H+ antiport by amiloride (1 mM) neither prevented the reduction of cathepsin activities nor the hypertrophy of the mesangial cells. Upon NH4Cl application lysosomal pH was elevated. This alkalinization may be causatively involved in the impairment of cathepsin B and L + B due to shifting the lysosomal pH above the optimum of their activities. In conclusion, NH4Cl induces hypertrophy but not hyperplasia in mesangial cells. This hypertrophy is caused by the reduction of protein degradation, mainly due to depressed activities of cathepsin B and L + B in the absence of enhanced protein synthesis. A shift of lysosomal pH above the optimum of the acidic cathepsins seems to be a key factor in their impaired activities in mesangial cells.

Ammonium Chloride↗