Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.23.15 (renin)
 35,795 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The contractility and distensibility of renal arterioles are important in the regulation of glomerular filtration. However, little is known regarding the characteristics of contractile proteins in these arterioles. Recently it was demonstrated that vascular smooth muscles contain two types of myosin heavy chain (MHC) isoforms, SM1 and SM2, which are unique molecular markers of smooth muscle cell phenotypes. SM1 is constitutively expressed in all types of smooth muscles, whereas SM2 exists only in mature smooth muscles. We characterized the expression of MHC isoforms as well as the ultrastructural myofilament assembly of renal arteriolar smooth muscles in human, rat and rabbit by immunohistochemical techniques. SM1 and alpha-smooth muscle actin were localized in both the preglomerular vessels (including the afferent arterioles) and efferent arterioles, whereas SM2 was present only in the preglomerular vessels. Renin-producing cells in the afferent arterioles (juxtaglomerular granular cells, JG cells) were positive for alpha-smooth muscle actin but negative for SM2. When renin synthesis was stimulated, the more proximal afferent arteriolar smooth muscles turned renin-positive and SM2 disappeared. Glomerular mesangial cells did not show immunoreactivities for SM1, SM2 or alpha-smooth muscle actin. The difference in MHC isoform expression in these arterioles was also reflected by ultrastructures; the afferent arteriolar smooth muscles contained abundant myofilaments including thick filaments, whereas the efferent arteriolar smooth muscles had a few myofilaments composed only of thin microfilaments. The JG cells displayed a myofilament assembly similar to that in the efferent arteriolar smooth muscles. We conclude from these observations that smooth muscles in pre-and postglomerular arterioles, the glomerular mesangial cells and JG cells differ in phenotypes, suggesting that they may have different contractile properties which may be critically involved in the regulation of glomerular filtration.
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PMID:Diversity and variability of smooth muscle phenotypes of renal arterioles as revealed by myosin isoform expression. 756 4

A study was undertaken to determine how variations in chronic pressure overload imposed on the left ventricle (LV) regulate both its mass and the relative level of expression of the slow beta-myosin heavy chain (MHC) in rodents. Systemic mean arterial pressure was varied by the following interventions: 1) abdominal aortic constriction (AbCon), 2) unilateral nephrectomy coupled with salt and deoxycorticoacetate treatment (Nx-D), and 3) treatment with the angiotensin II-converting enzyme inhibitor captopril (50 mg.kg-1.day-1) in combination with the other interventions. Results showed that both AbCon and Nx-D induced significant elevations in both beta-MHC protein and mRNA expression relative to the control state. beta-MHC expression (protein and mRNA) strongly correlated with blood pressure as well as LV mass over a wide range. Although captopril treatment significantly reversed the elevations in mean arterial pressure, LV mass, and beta-MHC content in the AbCon group, it had very little effect on these variables in the Nx-D group. Collectively, the results demonstrate that the expression of beta-MHC in the rodent heart is strongly dependent on the arterial pressure imposed on LV. Although the underlying mechanisms have not been elucidated fully as to how alterations in blood pressure are translated to the regulation of the beta-MHC gene expression, these findings suggest that the renin-angiotensin system is not an obligatory factor for inducing cardiac hypertrophy or beta-MHC expression in some models of hypertension.
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PMID:Pressure-induced regulation of myosin expression in rodent heart. 761 60

Previous studies show that elevations in blood pressure induce concomitant increases in both cardiac mass and slow beta-myosin heavy chain (MHC) expression in rodents, whereas caloric restriction of 50% (CR) causes an increase in beta-MHC while modestly lowering blood pressure in normotensive rats. The goals of this study were to 1) determine if beta-MHC expression could be independently regulated by CR and hypertension when these two interventions are combined and 2) determine if CR exerts a lowering of blood pressure in two contrasting models of rodent hypertension. Rodents were assigned to the following groups: 1) normal control (NC); 2) abdominal aortic constriction (Abcon), a model that induces hypertension via renin-angiotensin II; 3) nephrectomy-deoxycorticosterone acetate treatment (DOCA), a model that induces hypertension through increased salt retention; 4) CR; 5) Abcon+CR; 6) DOCA+CR. Results show that both Abcon and DOCA induced significant increases in systemic blood pressures, left ventricular (LV) weight/body weight, and the relative content of beta-MHC compared with NC. When applied in combination with either Abcon or DOCA, CR significantly blunted the changes observed in both systemic blood pressures and LV weight/body weight. In contrast, CR in conjunction with DOCA augmented % beta-MHC expression relative to either DOCA or CR alone. These data suggest 1) caloric restriction exerts a powerful impact on reducing experimentally induced hypertension in rodents and 2) the regulation of beta-MHC expression appears to be regulated by at least two processes, one associated with the stimulus of hypertension and the other involving an independent pathway linked to caloric restriction.
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PMID:Interaction of hypertension and caloric restriction on cardiac mass and isomyosin expression. 784 Mar 36

The renin-angiotensin system has been implicated as a possible mediator of the cardiac adaptations that develop in response to chronic pressure overload. In order to explore this, we studied rats that had elevated plasma renin activity (PRA) secondary to 6 weeks of either dietary salt restriction or renovascular hypertension (Htn)--conditions that exert distinctly different loads on the myocardium. Separate groups of sham and Htn animals were maintained on a high salt diet that resulted in a relative (Htn) or absolute (sham) reduction in PRA. Heart weight and heart/body weight ratios were increased only in animals with Htn. The ratio of alpha/beta myosin heavy chain (MHC) mRNA was significantly decreased with Htn. This ratio was markedly increased with low salt and was not influenced by high salt intake. Thus, the circulating renin-angiotensin system does not appear to play a primary role in defining cardiac myosin heavy chain adaptations to hemodynamic loads. However, sodium restriction, either via its hemodynamic or humoral effects, is sufficient to induce a physiologic change in myosin heavy chain gene expression in rats.
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PMID:The influence of dietary salt and plasma renin activity on myosin heavy chain gene expression in rat hearts. 839 98

Spontaneously hypertensive rats (SHR) of advanced age exhibit depressed myocardial contractile function and ventricular fibrosis, as stable compensated hypertrophy progresses to heart failure. Transition to heart failure in SHR aged 18-24 months was characterized by impaired left ventricular (LV) function, ventricular dilatation, and reduced ejection fraction without an increase in LV mass. Studies of papillary muscles from SHR with failing hearts (SHR-F), SHR without failure (SHR-NF), and age-matched Wistar Kyoto (WKY) rats allowed examination of changes in the mechanical properties of myocardium during the transition to heart failure. Papillary muscles of SHR-F exhibited increased fibrosis, impaired contraction, and decreased myocyte fractional area. These findings in papillary muscles were correlated with a higher concentration of hydroxyproline and increased histological evidence of fibrosis in the LV free wall. While a depression in active tension accompanied these structural alterations in papillary muscles, it was not evident when active tension was normalized to myocyte fractional area. Together, these data suggest that individual myocyte function may be preserved but that myocyte loss and replacement by extracellular matrix contribute substantially to the decrement in active tension. An absent or negative inotropic response to isoproterenol is observed in SHR-F and SHR-NF papillary muscles and may result in part from age-related alterations in beta-adrenergic receptor dynamics and a shift from alpha- to beta-myosin heavy chain (MHC) protein. During the transition to failure, ventricles of SHR exhibit a marked increase in collagen and fibronectin mRNA levels, suggesting that an increase in the expression of specific extracellular matrix genes may contribute to fibrosis, tissue stiffness, and impaired function. Transforming growth factor-beta 1 (TGF-beta 1) mRNA levels also increase in SHR-F, consistent with the concept that TGF-beta 1 plays a key regulatory role in remodelling of the extracellular matrix gene during the transition to failure. The renin-angiotensin-aldosterone system is also implicated in the transition to failure: SHR treated with the angiotensin converting enzyme inhibitor captopril starting at 12 months of age did not develop heart failure during the 18-24 month observation period. Captopril treatment that was initiated after rats were identified with evidence of failure led to a reappearance of alpha-MHC mRNA but did not improve papillary muscle function. Research opportunities include investigation of apoptosis as a mechanism of cell loss, delineation of the regulatory roles of TGF-beta 1 and the renin-angiotensin-aldosterone system in matrix accumulation, and studies of proteinase cascades that regulate matrix remodelling.
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PMID:The ageing spontaneously hypertensive rat as a model of the transition from stable compensated hypertrophy to heart failure. 868 57

We generated transgenic mice containing a chimeric construct consisting of the alpha-cardiac myosin heavy chain (alpha cMHC) promoter and the human renin (hRen) gene in order to target hRen synthesis specifically to the heart. The construct consisted of three segments: (i) an alpha cMHC DNA segment including 4.5 kb of 5' flanking DNA and an additional 1.1 kb of genomic DNA encompassing exons I-III (non-coding) and the first two introns; (ii) a partial hRen cDNA consisting of exons I-VI; and (iii) a hRen genomic segment containing exons VII through IX, their intervening introns, and 400 bp of 3' flanking DNA. This results in the formation of a 909 bp internal fusion exon consisting of alpha cMHC, polylinker, and hRen sequences. Despite the presence of splice acceptor and donor sites bracketing this exon, transcription of this transgene resulted in a major alternatively spliced mRNA lacking the exon and therefore a majority of the hRen coding sequence. Cloning and sequencing of RT-PCR products from several heart samples from two independent transgenic lines confirmed accurate and faithful splicing of alpha cMHC exon II to hRen exon VII thus bypassing the internal fusion exon. All other exons (alpha cMHC exons I and II and hRen exons VII, VIII and IX) were appropriately spliced. These results are consistent with the hypothesis on exon definition which states that internal exons have a size limitation. Moreover, the results demonstrate that transgenes present in the genome at independent insertion sites and in either a single copy or multiple copies can be subject to exon skipping. The implications for transgene design will be discussed.
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PMID:Inappropriate splicing of a chimeric gene containing a large internal exon results in exon skipping in transgenic mice. 891 7

Angiotensin II (AII), the principal mediator of the renin-angiotensin system, is an important regulator of vascular and cardiac homeostasis. AII has also been shown to be a regulator of cardiac hypertrophy and of the corresponding changes in amount and composition of certain tissue proteins. We examined the trophic effects of AII on cultured myocytes derived from neonatal rat ventricles and followed, by Northern blot analysis and polyacrylamide gel electrophoresis, the expression of alpha- and beta-myosin heavy chain iso-mRNAs and isoproteins. Our findings show that a single administration of AII is sufficient to induce a trophic response in cultured beating myocytes and to enhance the expression of beta-myosin heavy chain iso-mRNA and isoprotein, having no effect on alpha-myosin heavy chain. Induction of alpha-myosin heavy chain expression by thyroid hormone before AII was administered showed that AII could not potentiate a shift from alpha- to beta-myosin heavy chain predominance. We suggest that the potency of AII to regulate the expression of myosin heavy chain isogenes is restricted to the beta isoform and is overridden by thyroid hormone.
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PMID:The effect of angiotensin II on myosin heavy chain expression in cultured myocardial cells. 894 29

Chronic ventricular tachycardia (chronic VT) causes left ventricular (LV) dysfunction and is associated with increased LV wall stress and neurohormonal activation, but no LV hypertrophy. The mechanisms responsible for the lack of myocardial growth with chronic VT are unknown. Accordingly, this study examined contractile protein [myosin heavy chain (MHC)] synthesis in a rabbit model of chronic VT. MHC mRNA levels, protein concentration, and synthesis rates were examined in control rabbits (n = 18) and in rabbits with chronic VT (400 beats/min, 3 wk, n = 18). With chronic VT, LV end-diastolic volume increased (8.2 +/- 0.8 vs. 5.3 +/- 0.6 ml, P < 0.05), ejection fraction decreased (12 +/- 3 vs. 38 +/- 4%, P < 0.05) and peak systolic wall stress increased (963 +/- 93 vs. 262 +/- 42 g/cm2, P < 0.05). Plasma catecholamine and endothelin levels also increased threefold, and renin activity increased twofold. Despite these stimuli for hypertrophy, LV mass-to-body weight ratio was unchanged (1.15 +/- 0.07 vs. 1.25 +/- 0.05 g/kg). At the myocyte level, chronic VT caused myocyte lengthening (159.6 +/- 1.8 vs. 121.6 +/- 1.4 microm, P < 0.05), but a reduction in myocyte cross-sectional area (199 +/- 6 vs. 249 +/- 7 microm2, P < 0.0001), as well as a reduced velocity of shortening (42.6 +/- 1.6 vs. 74.1 +/- 2.8 microm/s, P < 0.05). Chronic VT resulted in a significant increase in the rate of MHC synthesis, but paradoxically, there was no change in LV MHC content. Despite increased MHC synthesis, relative levels of MHC mRNA were not increased in chronic VT (2.79 +/- 0.23 vs. 2.44 +/- 0.20 AU, relative to glyceraldehyde-3-phosphate dehydrogenase), suggesting an increase in MHC translational efficiency. These unique findings suggest accelerated degradative processes must contribute to the failure of myocardial growth in this model of LV dysfunction in which increased LV wall stress, neurohormonal activation, and increased protein synthesis occurred.
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PMID:Myosin heavy chain synthesis is increased in a rabbit model of heart failure. 912 61

The present study investigated whether functional, molecular, and biochemical alterations occurring in chronic heart failure can already be detected in compensated hypertensive cardiac hypertrophy. Force of contraction (isolated papillary muscle strip preparations), sarcoplasmic reticulum (SR) protein and myosin heavy chain isoform expression (Northern and Western blot analysis), myocardial fibrosis (collagen stains, hydroxyproline quantification), myocardial renin mRNA (RT-PCR), and angiotensin II levels and plasma aldosterone concentrations (radioimmunoassay) were studied in hypertrophied myocardium from transgenic rats harboring the mouse Ren-2d gene. Contraction and relaxation velocities of isolated papillary muscle strips were significantly reduced in cardiac hypertrophy. The beta-/alpha-myosin heavy chain ratio was significantly increased in the hypertrophied left ventricles, whereas SR Ca2+-ATPase (SERCA 2a) and phospholamban mRNA and protein levels were significantly decreased. The decrease in SERCA 2a was more pronounced than the decrease in phospholamban levels. There was no increased myocardial fibrosis. Left ventricular myocardial renin mRNA and angiotensin II concentrations, as well as plasma aldosterone levels, were higher in transgenic than in control rats. In hypertensive cardiac hypertrophy, myosin heavy chain isoform shift and reduction of SR protein levels are related to systolic and diastolic dysfunction, respectively. These alterations precede the development of myocardial fibrosis. Increased myocardial renin mRNA and angiotensin II concentrations suggest that an activated tissue renin-angiotensin system might contribute to these alterations. Since the alterations in compensated cardiac hypertrophy apparently precede those in chronic heart failure, they might accelerate the transition from hypertrophy to failure and could therefore be targets for pharmacological interventions.
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PMID:Contractile systolic and diastolic dysfunction in renin-induced hypertensive cardiomyopathy. 931 21

In an in vivo study, spontaneously hypertensive rats (SHR) were treated with an angiotensin II (Ang II) type 1 receptor antagonist of candesartan or hydralazine. Untreated SHR progressively developed severe hypertension, and treatment with candesartan or hydralazine decreased blood pressure. Candesartan reduced left ventricular (LV) weight, LV wall thickness, transverse myocyte diameter, the relative amount of V3 myosin heavy chain, and interstitial fibrosis, while treatment with hydralazine slightly prevented an increase in LV wall thickness, but did not exert a significant reduction on other parameters. In an in vitro study, neonatal rat cardiomyocytes were cultured on deformable silicone dishes. Stretching cardiomyocytes activated second messengers such as protein kinase C, Raf-1 kinase, and mitogen-activated protein (MAP) kinase, increasing protein synthesis, enhancing endothelin (ET)-1 release, activating the Na+/H+ ion exchanger. Moreover, pretreatment with candesartan diminished an increase in phenylalanine incorporation, MAP kinase activity, and c-fos gene expression induced by the stretching of cardiomyocytes. This suggests that the cardiac renin-angiotensin system is linked to the formation of pressure-overload hypertrophy and that Ang II increases the growth of cardiomyocytes by an autocrine mechanism. Finally, we examined the signalling pathways leading to MAP kinase activation both in cardiac myocytes and in cardiac fibroblasts. Ang II-evoked signal transduction pathways differed between cell types. In cardiac fibroblasts, Ang II activated MAP kinase through a pathway including the Gbetagamma subunit of Gi protein, Src, Shc, Grb2, and Ras, while Gq and protein kinase C were important in cardiac myocytes.
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PMID:Role of tissue angiotensin II in myocardial remodelling induced by mechanical stress. 1007 20


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