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PubMed1989

Regression of left ventricular hypertrophy in hypertension with alpha-adrenergic blockade: physiological basis and therapeutic implications.

Left ventricular hypertrophy may be a serious consequence of chronic untreated hypertension since it may accentuate the risk of congestive heart failure, arrhythmias, coronary ischaemias and sudden death. Although haemodynamic factors may play a role in the genesis of left ventricular hypertrophy, certain neurohumoral mechanisms such as the adrenergic nervous system may induce left ventricular hypertrophy in patients with hypertension. There is considerable evidence to implicate adrenergic activation in the pathogenesis of left ventricular hypertrophy. Thus, adrenergic blockade may have a favourable impact on the course of left ventricular hypertrophy. Recent studies discussed in this paper have demonstrated that postsynaptic alpha-adrenergic blockers cause a significant reduction in the left ventricular mass. It is concluded that alpha-adrenergic blockers can be added to the list of antihypertensive drugs which can cause regression of left ventricular hypertrophy in patients with hypertension.

Adrenergic beta-Antagonists↗
PubMed1989

Noradrenaline and cardiac hypertrophy in the rat: changes in morphology, blood pressure and ventricular performance.

Noradrenaline hydrochloride (160 micrograms base/kg per h) or vehicle were infused subcutaneously for 11 days into 35 male Wistar-Furth rats using osmotic minipumps. Chronic noradrenaline infusion produced moderate hypertrophy of both ventricles without causing tissue oedema. Left ventricular (LV) hypertrophy was concentric with no change in cavity volume, increased mass: volume ratio (approximately 50%) and increased fibre diameter (approximately 25%). In the conscious rat, noradrenaline produced only a slight increase in mean arterial pressure (13%) and heart rate (11%) but a marked increase in the variability of mean blood pressure (250%). The extent of LV hypertrophy was not related to the level of mean blood pressure or to its variability. In the anaesthetized rat, peak cardiac pumping ability was normal before and after cardiac autonomic blockade. Peak pressure-generating ability during aortic occlusion was increased in hypertrophied hearts before autonomic blockade but was similar to control rats after autonomic blockade. Chronic noradrenaline administration produces cardiac hypertrophy which has many similarities to hypertensive cardiac hypertrophy but no clear association with the level of blood pressure.

Animals↗
PubMed1992

Depressed inotropic response to beta-adrenoceptor agonists in the presence of advanced cardiac hypertrophy in hearts from rats with induced aortic stenosis and from spontaneously hypertensive rats.

OBJECTIVE: To study the inotropic response to beta-adrenoceptor stimulation in isolated hypertrophied hearts from hypertensive rats. DESIGN AND METHODS: Cardiac hypertrophy was induced in Wistar rats by stenosing the abdominal aorta. Functional responses to isoprenaline, dobutamine, terbutaline and salbutamol were measured in paced (5 Hz), aortically stenosed hearts (18-20 and 32-34 weeks of age) and compared with those of sham-operated spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats. RESULTS: Following aortic stenosis, which was accompanied by less hypertension than that sustained by SHR, the Wistar rat hearts showed more pronounced cardiac hypertrophy. An initially equal inotropic response to the beta-adrenoceptor agonists (18-20 weeks) was reduced to 45% at 32-34 weeks in SHR but not in WKY rat hearts. The response to beta-adrenoceptor stimulation in the hypertrophied Wistar rat hearts was reduced at 18-20 weeks to 30% and at 32-34 weeks to 10% of controls, respectively. The response by all hypertrophied hearts to forskolin and N,2'-O-dibutyryladenosine 3':5' monophosphate was also diminished. CONCLUSIONS: The impaired contractile response to beta-adrenoceptor agonism is more clearly related to cardiac hypertrophy than to hypertension.

Adrenergic beta-Agonists↗
PubMed1996

Altered contractile function in isoproterenol-induced hypertrophied rat heart.

OBJECTIVE: To study the calcium-dependent mechanisms contributing to altered contractile function in isoproterenol-induced ventricular hypertrophy of the rat heart. DESIGN: The force-interval relationship, systemic evaluation of changed contractile force and calcium sensitivity of the myofilaments were investigated using small trabecular muscle from hearts with isoproterenol-induced cardiac hypertrophy. METHODS: Cardiac hypertrophy was induced by daily subcutaneous injection of isoproterenol for 12 days. The calcium sensitivity of myofilaments was studied using non-ionic detergent (Triton-X-100)-skinned trabeculae. The contractile force was evaluated at various concentrations of extracellular calcium and muscle lengths. The force-interval relationship was used to reflect altered intracellular calcium handling. RESULTS: The isoproterenol-induced cardiac hypertrophy was associated with significantly enhanced contractile force at various concentrations of extracellular calcium and muscle lengths. Also, an amplified force-interval relationship in hypertrophied muscle at long rest intervals was found. However, this study revealed no change in calcium sensitivity of myofilaments. CONCLUSION: Altered intracellullar calcium handling contributes to enhanced contractile force in isoproterenol-induced cardiac hypertrophy.

Actin Cytoskeleton↗
PubMed1997

Pressure overload per se rather than cardiac angiotensin converting enzyme activity may be important in the development of rat cardiac hypertrophy.

OBJECTIVE: To investigate the roles of the renin-angiotensin system and blood pressure in cardiac hypertrophy caused by a pressure overload. METHODS: Cardiac hypertrophy was induced by constricting the abdominal aorta above the renal arteries. After they had been banded, the rats were treated with the lower (1 mg/kg per day) or the higher (10 mg/kg per day) dose of quinapril [an angiotensin converting enzyme (ACE) inhibitor], or the lower (1 mg/kg per day) or the higher (10 mg/kg per day) dose of TCV-116 [an angiotensin II (AngII) AT1 receptor antagonist], for 4 weeks. Then, we measured the mean blood pressure (MBP), body weight, left ventricular weight (LVW), and serum and cardiac ACE activities. RESULTS: The higher dose of quinapril and that of TCV-116 prevented left ventricular hypertrophy and MBP elevation. Both the higher and the lower doses of quinapril reduced the serum and cardiac ACE activities significantly, whereas the higher dose of TCV-116 reduced the cardiac ACE activity and increased the serum ACE activity. The lower dose of quinapril, however, exerted no significant effect on MBP and the LVW:body weight ratio, although it reduced the cardiac and serum ACE activities significantly. There was a significant positive correlation between the MBP and the LVW:body weight ratio regardless of the cardiac ACE activity in data from all groups (r = 0.676, P < 0.0001). CONCLUSIONS: Our data indicate the importance of the blood pressure as a determinant of cardiac hypertrophy because inhibition of cardiac ACE activity alone without lowering of the blood pressure is insufficient to prevent cardiac hypertrophy. Our results suggest the presence of other pathways for AngII production not mediated by ACE, or growth factors other than AngII in pressure-overload cardiac hypertrophy.

Angiotensin Receptor Antagonists↗
PubMed1999

Involvement of receptor-type tyrosine kinase gene families in cardiac hypertrophy.

OBJECTIVE: The activation of protein tyrosine kinases (PTKs) has been postulated to be involved in cell differentiation and proliferation. To elucidate the involvement of tyrosine kinase genes in normal and pathological conditions, we analysed the expression patterns of receptor-type PTKs in the normal and hypertensive hypertrophied heart in rats. MATERIALS AND METHODS: Hypertrophied and normal rat hearts were obtained from hypertensive rats; deoxycorticosterone acetate (DOCA)-salt and 2 kidney-1 clip (2K-1C), and their sham-operated rats, respectively. A reverse transcription-polymerase chain reaction (RT-PCR) was performed using degenerated primers which were designed from highly conserved regions in the catalytic domains of receptor-type PTKs. The PCR products were ligated into a sequence vector, and subcloned by transforming bacteria. To compare the expression level of these PTK mRNAs in the normal and hypertrophied heart, we performed semi-competetive RT-PCR and immunohistochemical and Western blot analyses. RESULTS: Nucleotide sequencing of approximately 80 clones of PTKs revealed 10 receptor-type, five nonreceptor-type and two unknown types in the rat heart. Tie-2/Tek, Ryk, insulin-like growth factor-I receptor were abundantly expressed in the rat heart as members of receptor-type PTKs. Immunohistochemistry and RT-PCR demonstrated the presence of platelet-derived growth factor (PDGF)-alpha receptor, PDGF-beta receptor and fibroblast growth factor-3 receptor in both normal and hypertrophied hearts. We also confirmed the presence of Flt-1, KDR/FIk-1, and their ligand vascular endothelial growth factor, c-Met and its ligand hepatocyte growth factor (HGF), and Tie-1, Tie-2/Tek by immunohistochemistry and RT-PCR. The coexpression of cardiac HGF and c-Met in hypertrophied hearts, especially in 2K-1 C rats, was induced more intensively than that in DOCA-salt rats. CONCLUSION: These findings suggest that HGF/c-Met interactions may play an important role in cardiac hypertrophy and remodeling, probably as a result of the activation of the local renin-angiotensin system.

Animals↗
PubMed1995

Cardiac hypertrophy in rats after intravenous administration of CI-959, a novel antiinflammatory compound: morphologic features and pharmacokinetic and pharmacodynamic mechanisms.

CI-959 is an antiallergic/antiinflammatory agent currently in development. In rats, daily bolus intravenous administration of CI-959 at doses > or = 10 mg/kg was associated with development of cardiac hypertrophy. There was no morphologic or biochemical evidence of myocyte injury, and cardiac hypertrophy rapidly reversed after treatment was discontinued. Cardiac hypertrophy was not evident when CI-959 was given orally or by continuous intravenous infusion with ALZA osmotic pumps. Maximum plasma drug concentrations (Cmax) were significantly higher when CI-959 was given by bolus intravenous injection, suggesting that cardiac effects were dependent on high Cmax concentrations. When neonatal rat cardiomyocytes were exposed to CI-959 in vitro, there was no evidence of myocyte enlargement or increased protein content. Cardiac hypertrophy was prevented by pretreatment with nonselective beta- and beta 1-selective adrenoceptor blockers as well as with central sympatholytics. beta 2- and alpha-adrenoceptor blockers were ineffective in preventing cardiac hypertrophy. Bolus intravenous CI-959 administration resulted in prolonged hypotension and associated increase in plasma catecholamine levels, with apparent inhibition of reflex tachycardia. We conclude that CI-959-associated cardiac hypertrophy in rats was not a direct drug effect but instead was probably mediated by endogenous catecholaminergic stimulation of cardiac beta 1-adrenoceptors.

Administration, Oral↗
PubMed1995

Alterations in energy metabolism of hypertrophied rat cardiomyocytes: influence of propionyl-L-carnitine.

Alterations in energy metabolism, reduced fatty acid oxidation, and cardiac carnitine content have been implicated in the evolution from compensated to decompensated cardiac hypertrophy. We determined high-energy nucleotide levels in hypertrophied quiescent cardiomyocytes isolated from rat hearts 4 weeks after banding of abdominal aorta. In hypertrophied quiescent cardiomyocytes, a decrease in ATP content (p = 0.03), and ratios of ATP/total adenine nucleotides and of ATP/ADP were observed, together with an increase in ADP. In addition, palmitate, but not glucose oxidation, was markedly reduced in hypertrophied myocytes. In the presence of 25 microM propionyl-L-carnitine (PLC) or L-carnitine (LC), palmitate oxidation was significantly stimulated in hypertrophied myocytes. The ATP/ADP ratio was significantly increased only with PLC. This effect was not due to an enhanced PLC uptake, since total PLC uptake was 50% lower than that of LC. Changes in the energy generating system of quiescent myocytes occur early in pressure overload hypertrophy, and these alterations can be attenuated by PLC.

Adenosine Diphosphate↗
PubMed2003

Inhibition of matrix metalloproteinases prevents cardiac hypertrophy induced by beta-adrenergic stimulation in rats.

Insulin-like growth factor (IGF) -I is one of the candidates for cardiac hypertrophy induced by beta-adrenergic stimulation. However, the mechanisms by which the biologic actions of IGF-I are regulated under this condition remain unclear. IGF-I becomes bioavailable for its receptors upon its dissociation from IGF-binding protein (IGFBP) through IGFBP degradation. Because matrix metalloproteinases (MMPs) have been implicated in the degradation of IGFBPs, the authors investigated the role of MMPs in the regulation of the IGF-I action through the degradation of IGFBPs in cardiac hypertrophy induced by beta-adrenergic stimulation. They examined the expression of MMPs in cardiac tissues of rats infused with isoproterenol (3 mg/kg per day), the effect of a MMP inhibitor, SI-27 (5 mg/rat per day), on cardiac hypertrophy, and the expression of IGF-I and IGFBP-3. MMP-1 and -2 activities increased and IGFBP-3 was degraded in heart hypertrophied by isoproterenol. MMP inhibition caused a regression in the myocyte hypertrophy in association with the suppression of both IGF-I protein in myocytes and the degradation of IGFBP-3 protein. These results suggest that the induction of myocyte hypertrophy by isoproterenol is mediated, at least in part, by a modulation of the IGF-I axis.

Animals↗
PubMed2005

Pitavastatin inhibits cardiac hypertrophy in a rat model of progressive renal injury.

Increased cardiovascular mortality is an unresolved problem of chronic renal failure. Cardiac hypertrophy, observed in many patients with chronic renal failure, is a major risk factor for cardiovascular death. The purpose of the present study was to examine the effects of pitavastatin on cardiac hypertrophy in a progressive renal injury rat model by subtotal nephrectomy (SNx). Because we previously reported that angiotensin II played a pivotal role in cardiac hypertrophy of SNx rats, we first investigated the effects of pitavastatin on angiotensin II-induced activation of extracellular signal-regulated kinase (ERK) and serum response element (SRE) DNA-binding activity using neonatal rat cardiomyocytes. Angiotensin II-induced ERK activation was attenuated by pretreatment with pitavastatin. Luciferase assay revealed that angiotensin II-induced increase in SRE DNA-binding activity was inhibited by pitavastatin. We next examined the effect of pitavastatin on cardiac hypertrophy of SNx rats in vivo. Treatment with pitavastatin prevented ERK activation and cardiac hypertrophy in SNx rats without changes in blood pressure. The increased expression of atrial natriuretic factor mRNA in SNx rat hearts was significantly attenuated by the treatment with pitavastatin. These results suggest that pitavastatin has a beneficial effect on cardiac hypertrophy in renal failure through preventing the activation of ERK.

Angiotensin II↗
PubMed2004

CREG, a new regulator of ERK1/2 in cardiac hypertrophy.

OBJECTIVES: The cellular repressor of E1A-stimulated genes (CREG), a mannose-6-phosphate-containing secreted glycoprotein, enhances differentiation and inhibits proliferation. In this study, our aim was to understand the role of CREG in cardiac hypertrophy. METHODS: Two models of cardiac hypertrophy were used: the in vivo pressure-overloaded rat cardiac hypertrophy and the in vitro stretched neonatal rat cardiomyocyte hypertrophy. CREG's function in cardiac cells was investigated after over-expression or antisense inhibition of CREG. RESULTS: We found reduced CREG expression in rat hearts after the in vivo overload, as shown by Northern blot analysis. CREG over-expression inhibited cardiac cell growth, as demonstrated by reduced protein content, cell area and ERK1/2 level in cultured neonatal rat cardiomyocytes, and by the reduced proliferation of cultured neonatal rat cardiac fibroblasts. Additionally, over-expression of CREG dampened the stretched cardiomyocyte hypertrophy through ERK1/2. On the other hand, the opposite effects were observed when CREG expression was decreased using antisense. This modulation of CREG expression resulted in no changes in the cardiomyocyte expressions of the hypertrophic or apoptotic signaling molecules such as protein kinase C (PKC) epsilon, PKC beta1, PKC alpha, PKC beta2, PKC delta, JNK1/2, p38, p53, Bax, Bcl2 and Fas. CONCLUSIONS: CREG was found to inhibit cardiac cell growth as a novel regulator of ERK1/2 and might participate in the development of cardiac hypertrophy under pressure overload. The insight that CREG inhibited the growth in rat hearts in vivo and in cardiac cells in vitro provides new clues for further investigation of the mechanism of heart remodeling.

Animals↗
PubMed2004

Protein kinase C and extracellular signal regulated kinase are involved in cardiac hypertrophy of rats with progressive renal injury.

Increased cardiovascular mortality is an unresolved problem in patients with chronic renal failure. Cardiac hypertrophy is observed in the majority of patients with chronic renal failure undergoing haemodialysis. However, the mechanisms, including signal transduction pathways, responsible for cardiac hypertrophy in renal failure remain unknown. We examined the subcellular localization of protein kinase C (PKC) isoforms and phosphorylation activities of 3 mitogen-activated protein (MAP) kinase families in hypertrophied hearts of progressive renal injury rat model by subtotal nephrectomy (SNx). We also examined the effects of a novel angiotensin II type-1 receptor antagonist, CS-866, on the PKC translocation, MAP kinase activity and cardiac hypertrophy in SNx rats. The left ventricle/body weight ratios were significantly larger in SNx rats than in sham rats at 1, 2, and 4 weeks after surgery. The translocation of PKCalpha and epsilon isoforms to membranous fraction was observed in SNx rat hearts at 1, 2, and 4 weeks after surgery. Activation of extracellular signal regulated kinase (ERK) 1/2, but not p38 MAP kinase and c-Jun N-terminal kinase (JNK), was observed at 1 and 2 weeks after surgery. Angiotensin II receptor blockade with CS-866 (1 mg kg-1 day-1) prevented cardiac hypertrophy, PKC translocation and ERK1/2 activation in SNx rats without significant changes in blood pressure. These data suggest that PKC and ERK1/2 are activated by an angiotensin II receptor-mediated pathway and might play an important role in the progression of cardiac hypertrophy in renal failure.

Angiotensin II Type 1 Receptor Blockers↗
PubMedDate not supplied

An antidiabetic thiazolidinedione induces eccentric cardiac hypertrophy by cardiac volume overload in rats.

1. To assess the involvement of volume overload in the development of cardiac hypertrophy during treatment with an antidiabetic thiazolidinedione, changes in cardiac anatomy and parameters of cardiac volume overload were evaluated in female Sprague-Dawley rats treated with the thiazolidinedione derivative T-174. 2. Two week administration of T-174 (13 and 114 mg/kg per day) increased absolute and relative heart weights by 11-24%, demonstrating the development of cardiac hypertrophy. There was no evidence of oedema in hearts from treated rats. 3. Both plasma and blood volumes were increased in T-174-treated rats without any changes in systolic blood pressure and heart rate, whereas haematocrit was decreased. In accordance with the existence of volume overload, both left ventricular end-diastolic pressure and right atrial pressure were increased. Morphometric analysis of hearts revealed that T-174 induced eccentric heart hypertrophy, as characterized by a small increase in wall thickness and a large increase in the chamber volume, which is characteristic of volume overload. Volume overload is suggested as the possible trigger mechanism because blood volume expansion preceded cardiac hypertrophy and there was a high correlation between heart weight and blood volume. 4. T-174-treated streptozotocin-induced diabetic rats also exhibited blood volume expansion and cardiac hypertrophy. 5. These findings suggest that cardiac volume overload is induced by plasma volume expansion and contributes to the development of eccentric cardiac hypertrophy during treatment with antidiabetic thiazolidinediones. Although thiazolidinediones are insulin-sensitizing agents, these cardiac effects are likely to be mediated independently of insulin.

Animals↗
PubMed1993

Differential response of hypertrophied rat hearts to various alpha 1-adrenoceptor agonists.

With respect to the heart, the prolonged existence of hypertension, both in man and in experimental animals is predominantly characterized by an increase in left ventricular myocardial mass. In this process, the autonomic nervous system plays an important role. Although endogenous catecholamine stimulation of the heart is mainly exerted via the beta-adrenoceptors, in several mammalian species, the stimulation of cardiac alpha 1-adrenoceptors also mediates positive inotropic actions. We investigated the functional responses of isolated hypertrophied hearts taken from spontaneously hypertensive rats (SHR) and rats with an induced aortic stenosis (ASR) to various alpha 1-adrenoceptor agonists and compared them with those from age matched Wistar Kyoto (WKY) and "sham" operated controls. Accordingly, we studied the functional response to: methoxamine (alpha 1), cirazoline (alpha 1) and phenylephrine (alpha 1 > beta 1). The inotropic response to the alpha 1-adrenoceptor agonists cirazoline and methoxamine proved to be significantly weaker in hypertrophied hearts from SHR and ASR than in non-hypertrophied hearts from WHY and "sham" operated controls (p < 0.05). The inotropic response to phenylephrine remained intact in hypertrophied myocardial tissue. However, it was significantly reduced when the hearts were pre-treated with the intracellular Ca(2+)-antagonists ryanodine and TMB-8. These findings show that the mechanism of sarcolemmal Ca2+ release, activated by phenylephrine, is still intact in the hypertrophied myocardial cell. In conclusion, these data show that cardiac hypertrophy, be it of genetical or mechanical origin, leads to a reduced response of the isolated heart to alpha 1-adrenoceptor stimulation.

Adrenergic alpha-Agonists↗
PubMed1995

Reduced muscarinic cholinoceptor density and sensitivity in various models of experimental cardiac hypertrophy.

1. In the present study we investigated functional and binding characteristics of muscarinic receptors in experimental cardiac hypertrophy. 2. As models of cardiac hypertrophy we used hearts of spontaneously hypertensive rats (SHR) and Wistar rats with surgically induced abdominal aorta stenosis (ASR). Wistar Kyoto rats (WKY) and sham operated Wistar rats were used as respective controls. 3. The hypertrophy was more pronounced in hearts of ASR compared to SHR, although the mean arterial pressure was found to be lower. 4. Isolated, perfused Langendorff heart preparations (paced with 5 Hz) from both groups of hypertrophied hearts were less sensitive to the muscarinic agonists oxotremorin and methacholine (P < 0.05, all n = 6) when compared with control organs. The maximal reduction in contractile force induced by methacholine was 59.3 +/- 4.5% in SHR and 41.6 +/- 3.4% in ASR hearts versus 26.4 +/- 4.1% and 25.0 +/- 2.6% in control organs, respectively. 5. The density (fmol/mg protein-1) of muscarinic receptors in membrane homogenates of hearts from SHR (127.6 +/- 11.5) was unchanged, whereas in hearts from ASR (221.0 +/- 8.9) it was found to be reduced (P < 0.05) when compared to the respective controls (142.5 +/- 14.7 and 308.8 +/- 16.1, respectively, all n = 6). 6. From the present data we conclude that cardiac hypertrophy results in a loss of sensitivity towards muscarinic receptor stimulation. A corresponding reduction of left ventricular receptor density could only be demonstrated in massively hypertrophied hearts of ASR.

Animals↗
PubMed1994

Lack of correlation of hypotensive effects with prevention of cardiac hypertrophy by perindopril after ligation of rat coronary artery.

1. The present study was designed to test the hypothesis that beneficial effects of angiotensin converting enzyme (ACE)inhibitors are independent of a fall in blood pressure in rat experimental heart failure following coronary ligation. 2. The animals were assigned randomly to six groups; sham operation, controls subjected to coronary ligation (control), coronary ligation plus chronic treatment with ACE inhibitors at non- and hypotensive doses; perindopril (0.2 or 2 mg kg-1 day-1) or enalapril (2 or 20 mg kg-1 day-1) for three weeks starting one week after the ligation. 3. Systemic blood pressure was measured every week during the experiments. At the end of the treatments, cardiac function and heart weight (an index of myocardial hypertrophy) were determined. In the other animals, ACE activities in plasma and tissues including heart, kidney, lung and blood vessels were measured. 4. In the controls, cardiac ACE activity, weight of right ventricle and left ventricular end-diastolic pressure (LVEDP) were higher compared to those in the sham-operated animals four weeks after the coronary ligation. However, ACE activities were not changed in plasma, kidney, lung and aorta by ligation of the coronary artery. 5. The chronic treatment with perindopril at a dose of 0.2 mg kg-1 day-1 inhibited the increase in ACE activity in cardiac tissue and suppressed the right ventricular hypertrophy without affecting systemic haemodynamics. In contrast, enalapril at a dose of 20 mg kg-1 day-1, but not 2 mg kg-1 day-1, prevented the development of the right ventricular hypertrophy. Enalapril at 20 mg kg-1 day-1 also lowered systemic blood pressure. 6. There is no significant correlation between systemic blood pressure and right ventricular hypertrophy at the end of the treatment with perindopril (r = 0.06) or enalapril (r = 0.1).7. These findings demonstrate that perindopril, an ACE inhibitor, prevents cardiac hypertrophy without affecting systemic blood pressure in the rat with heart failure after coronary ligation, and suggest that selective augmentation of ACE activity in cardiac tissue is involved in the progression of hypertrophy in this model.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2005

Mechanical stretch induces podocyte hypertrophy in vitro.

BACKGROUND: Increased intraglomerular pressure is a final pathway toward glomerulosclerosis in systemic hypertension, diabetes, and focal segmental glomerulosclerosis (FSGS). Increased intraglomerular pressure causes stress-tension, or stretch, on resident glomerular cells. However, the effects of stretch on podocyte growth, and the mechanisms that underlie this, have not been elucidated. METHODS: To test the hypothesis that stretch alters podocyte growth, cultured mouse podocytes were exposed to cyclic mechanical stretch created by vacuum; control cells were grown under similar conditions, but not exposed to stretch. Proliferation (cell cycle phases) and hypertrophy (forward light scatter) were measured in stretched and control podocytes by flow cytometry. The role of the cyclin-dependent kinase (CDK) inhibitors, p21 and p27, was examined by stretching podocytes isolated from p21 and p27 knockout (-/-) mice, and the role of specific signaling pathways was assessed by Western blot analysis and blocking studies. RESULTS: Our results showed that stretch reduced cell cycle progression in wild-type and single p27-/- podocytes and induced hypertrophy in these cells in all phases of the cell cycle at 24, 48, and 72 hours. In contrast, stretch did not induce hypertrophy in single p21-/- and double p21/p27-/- podocytes. Stretch-induced hypertrophy required cell cycle entry, and was prevented by specifically blocking extracellular signal-regulated kinase 1/2 (Erk1/2) or Akt. Although stretch increased p38 activation, inhibition of this pathway had no effect on hypertrophy. CONCLUSION: Mechanical stretch induces hypertrophy in podocytes in vitro in all phases of the cell cycle. This effect is cell cycle dependent, and requires p21, Erk1/2, and Akt. Stretch may play a role in podocyte injury when intraglomerular pressure is increased.

Animals↗
PubMed2003

Regional distribution of hyperpolarization-activated current (If) and hyperpolarization-activated cyclic nucleotide-gated channel mRNA expression in ventricular cells from control and hypertrophied rat hearts.

Hyperpolarization-activated inward current (If) and changes in the messenger RNA (mRNA) expression levels of hyperpolarization-activated cyclic nucleotide-gated channel (HCN)2 and HCN4 encoding If channels of the rat heart were studied in control and hypertrophied myocytes isolated from three ventricular regions: the septum (S), the left ventricular free wall (LV) and the right ventricular free wall (RV). Electrophysiological experiments were conducted by ruptured and perforated-patch clamp techniques and quantification of mRNA levels was carried out by quantitative reverse transcriptase polymerase chain reaction. The occurrence, density and maximal specific conductance of If were found to be significantly higher in hypertrophied ventricular myocytes isolated from S and LV than in those isolated from RV or sham-operated rats. Half-maximal activation potential, the slope of the activation curve and the threshold for activation were similar in ventricular myocytes from sham and aortic stenosed rats in the three regions studied. Isoproterenol 1 micromol l-1 increased current size by shifting current activation to more positive potentials in both sham and hypertrophied myocytes. When we studied the mRNA levels of If channel isoforms present in the ventricle, we found a significant increase of HCN2 and HCN4 mRNA levels in hypertrophied myocytes from S and LV but not in RV. We conclude that the occurrence, density and conductance of If is higher in hypertrophied than in control ventricular myocytes, S being the region where all these changes were most evident. These findings are associated with a higher expression of HCN2 and HCN4 mRNA levels in the two regions that developed hypertrophy.

Action Potentials↗