Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.15.1 (ACE)
18,300 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Heart dysfunction in chronic diabetes has been observed to be associated with depressed myofibrillar adenosine triphosphatase activities as well as abnormalities in the sarcoplasmic reticular and sarcolemmal calcium transport processes. The evidence has been presented to show that alterations in the expression of myosin isozymes and regulatory proteins as well as myosin phosphorylation contribute to the development of myofibrillar remodeling in the diabetic heart. Defects in sarcoplasmic reticular and sarcolemmal calcium transport appear to be due to the accumulation of lipid metabolites in the membrane. Different agents, such as calcium-antagonists, beta-adrenoceptor blockers, angiotensin converting enzyme inhibitors, metabolic interventions and antioxidants, have been reported to exert beneficial effects in preventing subcellular remodeling and cardiac dysfunction in chronic diabetes. Clinical and experimental investigations have suggested that increased sympathetic activity, activated cardiac renin-angiotensin system, myocardial ischemia/functional hypoxia and elevated levels of glucose for a prolonged period, due to insulin deficiency, result in oxidative stress. It is proposed that oxidative stress associated with a deficit in the status of the antioxidant defense system may play a critical role in subcellular remodeling, calcium-handling abnormalities and subsequent diabetic cardiomyopathy.
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PMID:Subcellular remodeling and heart dysfunction in chronic diabetes. 989 15

In view of the activation of renin-angiotensin system under conditions associated with pressure overload on the heart, we examined the effects of captopril, an angiotensin converting enzyme inhibitor, and losartan, an angiotensin II receptor antagonist, on cardiac function, myofibrillar ATPase and sarcoplasmic reticular (SR) Ca2+-pump (SERCA2) activities, as well as myosin and SERCA2 gene expression in hypertrophied hearts. Cardiac hypertrophy was induced in rats treated with or without captopril or losartan by banding the abdominal aorta for 8 weeks; sham operated animals served as control. Decrease in left ventricular developed pressure, +dP/dt and -dP/dt as well as increase in left ventricular end diastolic pressure and increased muscle mass due to pressure overload were prevented by captopril or losartan. Treatment of animals with captopril or losartan also attenuated the pressure overload-induced depression in myofibrillar Ca2+-stimulated ATPase, myosin ATPase, SR Ca2+-uptake and SR Ca2+-release activities. An increase in beta-myosin heavy chain mRNA and a decrease in alpha-myosin heavy chain mRNA as well as depressed SERCA2 protein and SERCA2 mRNA levels were prevented by captopril or losartan. These results suggest that both captopril and losartan improve myocardial function in cardiac hypertrophy by preventing changes in gene expression and subsequent subcellular remodeling due to pressure overload.
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PMID:Modification of cardiac subcellular remodeling due to pressure overload by captopril and losartan. 1005 50

The importance of endogenous and exogenous estrogen levels to the development of cardiovascular disease in women in controversial. The purpose of our study was to examine the effect of estrogen on the development of hypertension, cardiac hypertrophy, ventricular function, and gene expression for atrial natriuretic peptide (ANP) and components of the renin angiotensin system in spontaneously hypertensive heart failure rats (SHHF/Mcc- facp). Development of hypertension was prevented in 3-month-old ovariectomized rats receiving subcutaneous 17 beta -estradiol implants (EST) compared to ovariectomized (OVX) and controls (CON). EST had the least left ventricular hypertrophy, CON were intermediate, and OVX had the most (P<0.05), correlating well with systolic blood pressure. OVX had significantly lower percentage V(1)myosin isoform compared to EST and CON, indicating reversion to a more immature phenotype associated with hypertrophy. Similarly, OVX had decreased percentage left ventricular shortening fraction by echocardiography compared to EST and CON. These changes were not accompanied by alterations in plasma ANP, or in expression of mRNA for left ventricular ANP, renal renin, or hepatic angiotensinogen. Serum angiotensin converting enzyme activity was lower in EST compared to CON or OVX. When 17 beta -estradiol was given to 17-month-old rats that had naturally ceased estrous cycling, there was no effect on hypertension, progression of cardiac functional decline, or survival. In conclusion, estradiol treatment given prior to the development of hypertension in SHHF prevented left ventricular hypertrophy and hypertension. Development of congestive heart failure was not delayed if 17 beta -estradiol was begun in the post-menopausal period. Effectiveness of estrogen therapy may depend on age or whether hypertension is already established at the time treatment is begun.
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PMID:Effect of ovariectomy and estrogen replacement on cardiovascular disease in heart failure-prone SHHF/Mcc- fa cp rats. 1042 50

Besides the reduction of angiotensin II formation, locally increased kinins may play a role in the cardiovascular action of angiotensin converting enzyme (ACE) inhibitors. To characterize the contribution of bradykinin to the effects of ACE inhibition by captopril on the development of pressure overload hypertrophy, sham-operated rats and rats with ascending aortic constriction were treated with captopril (80 mg/kg/day) or captopril and B2 kinin receptor antagonist HOE 140 (0.5 mg/kg/day) for 7 weeks. Left ventricular mass and geometry, hydroxyproline concentration and myosin isozymes (marker of a fetal phenotype) were assessed. Rats with aortic constriction exhibited a marked increase in left ventricular weight and diastolic pressure-volume relationship was shifted to smaller volumes. Signs of congestive heart failure were not apparent. The hydroxyproline concentration remained unaltered. However, the proportion of isomyosin V3 was increased (p < 0.05). Administration of captopril reduced (p < 0.05) systolic blood pressure, body and cardiac weight in all treated rats. The reduction of left ventricular weight was disproportionally higher in pressure overloaded rats, thus the relative left ventricular weight decreased by 15% (p < 0.05). Captopril augmented the isomyosin V1 expression (p < 0.05) in sham operated as well as pressure overloaded rats. The isomyosin V1 percentage was inversely related to the relative left ventricular weight. Two different (p < 0.05) correlation lines were detected for untreated and captopril treated rats. None of captopril associated effects were removed by simultaneously administered B, kinin receptor antagonist HOE 140. Thus, stimulation of bradykinin B2 receptor appears not to mediate the effects of captopril on cardiac growth and contractile proteins during the development of pressure overload hypertrophy.
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PMID:Bradykinin (B2) independent effect of captopril on the development of pressure overload cardiac hypertrophy. 1110 54

For the management of chronic heart failure, both angiotensin converting enzyme inhibitors (ACEI) and angiotensin II type 1 receptor blockers (ARB) are useful, however, the differences between the two groups of agents are unclear. We compared the effects of long-term treatment with an ACEI (imidapril) and an ARB (TA-606) in rats that had recovered from experimental autoimmune myocarditis (EAM). Forty-two Lewis rats were immunized with porcine cardiac myosin on day 0 and divided into 6 groups, group C (distilled water), group IL (imidapril 0.5 mg/kg/day), group IH (imidapril 2 mg/kg/day), group TL (TA-606 2 mg/kg/day), group TH (TA-606 6 mg/kg/day), and group IT (imidapril 0.5 mg/kg/day + TA-606 2 mg/kg/day). Drugs were administered from day 28. Hemodynamic parameters, heart weight/body weight ratio (HW/BW), and area of fibrosis were measured on days 70-74. Only the high dose of imidapril significantly decreased central venous pressure and significantly increased maximum dP/dt and the absolute value of minimum dP/dt. HW/BW was suppressed in groups IH, TH, and IT. Thus, in treatment of chronic heart failure in rats, a sufficient dose of ACEI was needed to improve hemodynamics and to prevent ventricular hypertrophy. The hemodynamic effects of ARB and combination therapy of both drugs at low doses were not significant.
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PMID:Effects of imidapril and TA-606 on rat dilated cardiomyopathy after myocarditis. 1458 55

Chronic heart failure is a slowly progressive disease. Hemodynamic deterioration activates various neuro-humoral factors and increases stresses, such as catecholamine, angiotensin II (AII), cytokines, endothelin, wall stress, ischemia, tachycardia, and oxidative stress. These factors affect the myocardium to cause phenotype switching, leading to ventricular remodeling. We investigated the effects of pharmacological blocking for neuro-humoral factors in rats with dilated cardiomyopathy. Experimental autoimmune myocarditis (EAM) was elicited in Lewis rats by immunization with cardiac myosin. After acute inflammation healed, rats were treated with angiotensin converting enzyme inhibitors (ACEI), type 1 AII receptor blockers, and amiodarone. These agents had favorable effects on hemodynamics and myocardial contractility, prevented fibrosis, suppressed the expression of ANP, and reversed phenotypic change of cardiac myosin. AII receptor blockers were less effective than ACEI. In order to prevent ventricular remodeling in chronic heart failure, wide and complete blocking of neuro-humoral factors is important.
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PMID:[Effects of humoral factors on left ventricular remodeling under chronic heart failure]. 1474 25

Congestive heart failure (CHF) is characterized by abnormal vasoconstriction and an impairment in nitric oxide (NO)-mediated vasodilatation. We have previously demonstrated that the decrease in sensitivity to NO lies at least partially at the level of the smooth muscle and is due to a reduction in the relative expression of the leucine zipper positive (LZ(+)) isoform of the myosin targeting subunit (MYPT1) of myosin light chain phosphatase. We hypothesized that since the attenuated vasodilatory response to NO in CHF has been shown to be secondary to an increased activity of the renin-angiotensin system, angiotensin converting enzyme (ACE) inhibition could affect MYPT1 isoform expression. To test this hypothesis, a rat myocardial infarction (MI) model of CHF was used; following left coronary artery ligation, rats were divided into control and captopril-treated groups. A third group of rats was given prazosin for 4 weeks. In the untreated control group, left ventricular function (LVF) was reduced at 2 weeks post-MI and remained at this level. Captopril treatment attenuated the fall in LVF. In the control aorta and iliac artery, the expression of the LZ(+) MYPT1 isoform fell 44-52% between 2 and 4 weeks post-MI, whereas in animals treated with captopril, MYPT1 isoform expression did not change. A decrease in the sensitivity to cGMP-mediated smooth muscle relaxation occurred coincident with the decrease in LZ(+) MYPT1 expression. The change in LZ(+) MYPT1 expression was not due to the decrease in afterload, as prazosin therapy produced an improvement in LVF but did not increase the relative expression of LZ(+) MYPT1 isoform. These data suggest that ACE inhibition, unique from pure afterload reduction, prevents MYPT1 isoform switching, which would preserve normal flow, or NO-mediated vasodilatation.
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PMID:Captopril prevents myosin light chain phosphatase isoform switching to preserve normal cGMP-mediated vasodilatation. 1681 32

The angiotensin converting enzyme inhibitor captopril prevents myosin-induced experimental autoimmune myocarditis. Captopril inhibits production of angiotensin II and increases bradykinin signaling, among other actions. To test whether captopril inhibits disease through blockade of angiotensin signaling, we tested the ability of losartan, an angiotensin II receptor blocker, to prevent myosin-induced myocarditis. A/J mice immunized with the heavy chain of cardiac myosin in complete Freund's adjuvant develop acute myocarditis by day 21 post-immunization, consisting of severe focal inflammation, necrosis and fibrosis. Administration of losartan (250 mg/L in the drinking water) or captopril (75 mg/L in the drinking water) significantly reduced inflammation, necrosis and fibrosis in myosin-immunized mice. The heart weights and the heart weight-to-body weight ratios were also significantly reduced in both treatment groups. However, whereas captopril reduced myosin-specific delayed-type hypersensitivity, losartan did not. Both captopril-treated mice and losartan-treated mice showed a decrease in myosin-specific autoantibody production. Because losartan treatment significantly reduced myocarditis, fibrosis and autoantibody production in EAM, it is likely that prevention of angiotensin II receptor stimulation is a major mechanism underlying the inhibition of myosin-induced myocarditis by captopril.
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PMID:Comparison of angiotensin converting enzyme inhibition and angiotensin II receptor blockade for the prevention of experimental autoimmune myocarditis. 1758 93

Congestive heart failure (CHF) is characterized by increased vascular tone and an impairment in nitric-oxide-mediated vasodilatation. We have demonstrated that the blunted response to nitric oxide is due, in part, to a reduction in the leucine-zipper-positive isoform of the myosin-targeting subunit (MYPT1) of myosin light-chain phosphatase. Additionally, we have shown that angiotensin-converting enzyme inhibition, but not afterload reduction with prazosin, preserves leucine-zipper-positive MYPT1 isoform expression in vascular smooth muscle cells and normalizes the sensitivity to cGMP-mediated vasodilatation. We therefore hypothesized that in CHF, growth regulators and cytokines downstream of the angiotensin II receptor are involved in modulating gene expression in vascular tissue. Rats were divided into control and captopril-treated groups following left coronary artery ligation. Gene expression profiles in the aorta and portal vein at baseline and 2 and 4 weeks after myocardial infarction (MI) were analyzed using microarray technology and quantitative real-time PCR. After MI, microarray analysis revealed differential mRNA expression of 21 genes in the aorta of captopril-treated rats 2 and 4 weeks after surgery when compared to gene expression profiles at baseline and without captopril therapy. Real-time PCR demonstrated that captopril suppressed the expression of protein kinases in the angiotensin-II-mediated mitogen-activated protein kinase signaling pathway, including Taok1 and Raf1. These data suggest that in CHF, captopril therapy modulates gene expression in vascular smooth muscle, and some of the beneficial effects of ACE inhibition may be due to differential gene expression in the vasculature.
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PMID:Gene expression profiles of vascular smooth muscle show differential expression of mitogen-activated protein kinase pathways during captopril therapy of heart failure. 1841 3

The clinical syndrome of heart failure is associated with both a resting vasoconstriction and reduced sensitivity to nitric oxide mediated vasodilatation, and this review will focus on the role of myosin light chain (MLC) phosphatase in the pathogenesis of the vascular abnormalities of heart failure. Nitric oxide mediates vasodilatation by an activation of guanylate cyclase and an increase in the production of cGMP, which leads to the activation of the type I cGMP-dependent protein kinase (PKGI). PKGI then activates a number of targets that produce smooth muscle relaxation including MLC phosphatase. MLC phosphatase is a holoenzyme consisting of three subunits; a 20 kD subunit of unknown function, an approximately 38-kD catalytic subunit and a myosin targeting subunit (MYPT1). Alternative splicing of a 31 bp 3 exon generates MYPT1 isoforms, which differ by a COOH-terminus leucine zipper (LZ). Further, PKGI-mediated activation of MLC phosphatase requires the expression of a LZ+ MYPT1. Congestive heart failure is associated with a decrease in LZ+ MYPT1 expression, which results in a decrease in the sensitivity to cGMP-mediated smooth muscle relaxation. Beyond their ability to reduce afterload, angiotensin converting enzyme (ACE) inhibitors have a number of beneficial effects that include maintaining the expression of the LZ+ MYPT1 isoform, thereby conserving normal sensitivity to cGMP-mediated vasodilatation, as well as differentially regulating genes associated with mitogen activated protein kinase (MAPK) signalling. ACE inhibition reduces circulating angiotensin II and thus limits the downstream activation of MAPK signalling pathways, possibly preventing the alteration of the vascular phenotype to preserve normal vascular function.
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PMID:The potential role of MLC phosphatase and MAPK signalling in the pathogenesis of vascular dysfunction in heart failure. 1912 Jul


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