Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. This study was undertaken to determine whether the AT1 receptor directly contributes to hypertension-induced cardiac hypertrophy and gene expressions. 2. Stroke-prone spontaneously hypertensive rats (SHRSP) were given orally an AT1, receptor antagonist (losartan, 30 mg kg-1 day-1), an angiotensin converting enzyme inhibitor (enalapril 10 mg kg-1 day-1), a dihydropyridine calcium channel antagonist (amlodipine, 5 mg kg-1 day-1), or vehicle (control), for 8 weeks (from 16 to 24 weeks of age). The effects of each drug were compared on ventricular weight and mRNA levels for myocardial phenotype- and fibrosis-related genes. 3. Left ventricular hypertrophy of SHRSP was accompanied by the increase in mRNA levels for two foetal phenotypes of contractile proteins (skeletal alpha-actin and beta-myosin heavy chain (beta-MHC)), atrial natriuretic polypeptide (ANP), transforming growth factor-beta-1 (TGF-beta 1) and collagen, and a decrease in mRNA levels for an adult phenotype of contractile protein (alpha-MHC). Thus, the left ventricle of SHRSP was characterized by myocardial transition from an adult to a foetal phenotype and interstitial fibrosis at the molecular level. 4. Although losartan, enalapril and amlodipine lowered blood pressure of SHRSP to a comparable degree throughout the treatment, losartan caused regression of left ventricular hypertrophy of SHRSP to a greater extent than amlodipine (P < 0.01). 5. Losartan significantly decreased mRNA levels for skeletal alpha-actin, ANP, TGF-beta 1 and collagen types I, III and IV and increased alpha-MHC mRNA in the left ventricle of SHRSP. Amlodipine did not alter left ventricular ANP, alpha-MHC and collagen types I and IV mRNA levels of SHRSP. 6. The effects of enalapril on left ventricular hypertrophy and gene expressions of SHRSP were similar to those of losartan, except for the lack of inhibition of collagen type I expression by enalapril. 7. Unlike the hypertrophied left ventricle, there was no significant difference between losartan and amlodipine in the effects on non-hypertrophied right ventricular gene expressions of SHRSP. 8. Our results show that hypertension causes not only left ventricular hypertrophy but also molecular transition of myocardium to a foetal phenotype and interstitial fibrosis-related molecular changes. These hypertension-induced left ventricular molecular changes may be at least in part mediated by the direct action of local angiotensin II via the AT1, receptor.
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PMID:Effects of an AT1 receptor antagonist, an ACE inhibitor and a calcium channel antagonist on cardiac gene expressions in hypertensive rats. 876 77

Previous studies have suggested that angiotensin II (Ang II) modulates cardiac contractility, rhythm, metabolism, and structure. However, it is unclear whether the cardiac effects are due to direct actions of Ang II on the myocardium or if they are due to secondary effects mediated through the hemodynamic actions of Ang II. In this study, we used the alpha-myosin heavy chain (alphaMHC) promoter to generate transgenic mice overexpressing angiotensin II type 1 (AT1a) receptor selectively in cardiac myocytes. The specificity of transgene expression in the transgenic offspring was confirmed by radioligand binding studies and reverse transcription-PCR. The offspring displayed massive atrial enlargement with myocyte hyperplasia at birth, developed significant bradycardia with heart block, and died within the first weeks after birth. Thus, direct activation of AT1 receptor signaling in cardiac myocytes in vivo is sufficient to induce cardiac myocyte growth and alter electrical conduction.
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PMID:Overexpression of angiotensin AT1 receptor transgene in the mouse myocardium produces a lethal phenotype associated with myocyte hyperplasia and heart block. 917 28

The present study was undertaken to examine the effects of volume overload on cardiac gene expression and the possible role of angiotensin AT1 receptor in such expression. Cardiac volume overload was prepared by abdominal aortocaval shunt in rats. Rats with aortocaval shunt were treated with 1) vehicle, 2) an angiotensin AT1 receptor antagonist, CS-866 (10 mg/kg/d), or 3) an angiotensin-converting enzyme inhibitor, temocapril (10 mg/kg/d), for 7 days. Cardiac tissue mRNA was measured by Northern blot analysis with specific probes. Aortocaval shunt not only caused cardiac hypertrophy but also upregulated the gene expression of atrial natriuretic polypeptide, collagen III, and downregulated Ca(2+)-ATPase expression in the left ventricle. These changes were prevented by treatment with CS-866, while temocapril failed to normalize left ventricular Ca(2+)-ATPase expression. Unlike the left ventricle, the significant downregulation of alpha-myosin heavy chain and transforming growth factor-beta 3 by aortocaval shunt was observed in the right ventricle, and CS-866 normalized this decreased expression of transforming growth factor-beta 3. The left and right atria showed increased expression of collagen type I as well as of collagen type III and atrial natriuretic polypeptide, and these increases were more effectively prevented by CS-866 than by temocapril. Thus, the effects of cardiac volume overload on cardiac performance-related gene expression differ between the ventricles and atria. Our results suggest that AT1 receptor partially contributed to volume overload-induced changes in cardiac gene expression and that AT1 receptor antagonists and angiotensin-converting enzyme inhibitors have different effects in this model of cardiac hypertrophy.
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PMID:Effects of angiotensin AT1 receptor antagonist on volume overload-induced cardiac gene expression in rats. 922 Feb 78

Angiotensin (Ang) II has two major receptor isoforms, AT1 and AT2. Currently, AT1 antagonists are undergoing clinical trials in patients with cardiovascular diseases. Treatment with AT1 antagonists causes elevation of plasma Ang II which selectively binds to AT2 and exerts as yet undefined effects. Cardiac AT2 level is low in adult hearts, whereas its distribution ratio is increased during cardiac remodeling and its action is enhanced by application of AT1 antagonists. Although in AT2 knock-out mice sensitivity to the pressor action of Ang II was increased, underlying mechanisms remain undefined. Here, we report the unexpected finding that cardiac-specific overexpression of the AT2 gene using alpha-myosin heavy chain promoter resulted in decreased sensitivity to AT1-mediated pressor and chronotropic actions. AT2 protein undetectable in the hearts of wild-type mice was overexpressed in atria and ventricles of the AT2 transgenic (TG) mice and the proportions of AT2 relative to AT1 were 41% in atria and 45% in ventricles. No obvious morphological change was observed in the myocardium and there was no significant difference in cardiac development or heart to body weight ratio between wild-type and TG mice. Infusion of Ang II to AT2 TG mice caused a significantly attenuated increase in blood pressure response and the change was completely blocked by pretreatment with AT2 antagonist. This decreased sensitivity to Ang II-induced pressor action was mainly due to the AT2-mediated strong negative chronotropic effect and exerted by circulating Ang II in a physiological range that did not stimulate catecholamine release. Isolated hearts of AT2 transgenic mice perfused using a Langendorff apparatus also showed decreased chronotropic responses to Ang II with no effects on left ventricular dp/dt max values, and Ang II-induced activity of mitogen-activated protein kinase was inhibited in left ventricles in the transgenic mice. Although transient outward K+ current recorded in cardiomyocytes from AT2 TG mice was not influenced by AT2 activation, this study suggested that overexpression of AT2 decreases the sensitivity of pacemaker cells to Ang II. Our results demonstrate that stimulation of cardia AT2 exerts a novel antipressor action by inhibiting AT1-mediated chronotropic effects, and that application of AT1 antagonists to patients with cardiovascular diseases has beneficial pharmacotherapeutic effects of stimulating cardiac AT2.
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PMID:Cardiac-specific overexpression of angiotensin II AT2 receptor causes attenuated response to AT1 receptor-mediated pressor and chronotropic effects. 944 84

Previous studies have shown that the renin-angiotensin system (RAS) is activated in diabetes and this may contribute to the subcellular remodelling and heart dysfunction in this disease. Therefore, we examined the effects of RAS blockade by enalapril, an angiotensin-converting enzyme inhibitor, and losartan, an angiotensin receptor AT1 antagonist, on cardiac function, myofibrillar and myosin ATPase activity as well as myosin heavy chain (MHC) isozyme expression in diabetic hearts. Diabetes was induced in rats by a single injection of streptozotocin (65 mg/kg; i.v.) and these animals were treated with and without enalapril (10 mg/kg/day; oral) or losartan (20 mg/kg/day; oral) for 8 weeks. Enalapril or losartan prevented the depressions in left ventricular rate of pressure development, rate of pressure decay and ventricular weight seen in diabetic animals. Both drugs also attenuated the decrease in myofibrillar Ca2+-ATPase, Mg2+-ATPase and myosin ATPase activity seen in diabetic rats. The diabetes-induced increase in beta-MHC content and gene expression as well as the decrease in alpha-MHC content and mRNA levels were also prevented by enalapril and losartan. These results suggest the occurrence of myofibrillar remodelling in diabetic cardiomyopathy and provide evidence that the beneficial effects of RAS blockade in diabetes may be associated with attenuation of myofibrillar remodelling in the heart.
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PMID:Renin-angiotensin blockade attenuates cardiac myofibrillar remodelling in chronic diabetes. 1536 13

This chapter describes the methods required for overexpression of the angiotensin II type I receptor (AT1) in cardiomyocytes of transgenic rats. This includes cloning of the transgenic construct consisting of the alpha-myosin heavy chain (MHC) promoter, the human AT1 cDNA and SV40 T-antigen splicing and polyadenylation sites, and purification of the transgenic DNA for microinjection by electroelution. The individual steps for the introduction of the transgene into the germline of rats by pronuclear microinjection are described, with special emphasis on the adaptation made to the standard procedure in mice. The identification of transgenic rats by PCR and Southern blot and the principles of establishing transgenic lines as well as characterizing transgene expression by Northern blot and RT-PCR are outlined.
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PMID:Cardiac-specific overexpression of angiotensin II type 1 receptor in transgenic rats. 1601 32

Resistance training is accompanied by cardiac hypertrophy, but the role of the renin-angiotensin system (RAS) in this response is elusive. We evaluated this question in 36 male Wistar rats divided into six groups: control (n=6); trained (n=6); control+losartan (10 mg.kg(-1).day(-1), n=6); trained+losartan (n=6); control+high-salt diet (1%, n=6); and trained+high-salt diet (1%, n=6). High salt was used to inhibit the systemic RAS and losartan to block the AT1 receptor. The exercise protocol consisted of: 4x12 bouts, 5x/wk during 8 wk, with 65-75% of one repetition maximum. Left ventricle weight-to-body weight ratio increased only in trained and trained+high-salt diet groups (8.5% and 10.6%, P<0.05) compared with control. Also, none of the pathological cardiac hypertrophy markers, atrial natriuretic peptide, and alphaMHC (alpha-myosin heavy chain)-to-betaMHC ratio, were changed. ACE activity was analyzed by fluorometric assay (systemic and cardiac) and plasma renin activity (PRA) by RIA and remained unchanged upon resistance training, whereas PRA decreased significantly with the high-salt diet. Interestingly, using Western blot analysis and RT-PRC, no changes were observed in cardiac AT2 receptor levels, whereas the AT1 receptor gene (56%, P<0.05) and protein (31%, P<0.05) expressions were upregulated in the trained group. Also, cardiac ANG II concentration evaluated by ELISA remained unchanged (23.27+/-2.4 vs. 22.01+/-0.8 pg/mg, P>0.05). Administration of a subhypotensive dose of losartan prevented left ventricle hypertrophy in response to the resistance training. Altogether, we provide evidence that resistance training-induced cardiac hypertrophy is accompanied by induction of AT1 receptor expression with no changes in cardiac ANG II, which suggests a local activation of the RAS consistent with the hypertrophic response.
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PMID:AT1 receptor participates in the cardiac hypertrophy induced by resistance training in rats. 1849 27