Angiotensin-converting enzymes and drug discovery in cardiovascular diseases

Shi, Lijun; Mao, Caiping; Xu, Zhice; Zhang, Li

doi:10.1016/j.drudis.2010.02.003

Cited by 57 publications

(49 citation statements)

References 102 publications

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“…Mammalian ACE activity in the ChP4 was high and localized to the BBM (5,7,59). Although ACE2 and NEP mRNA were detected in the ChP, we are not aware of any studies measuring their relative activity (21,72). We found that ACE2 activity was 3.5-fold higher than ACE and 2.4-fold higher than NEP.…”

Section: Control Bmxmentioning

confidence: 59%

Antenatal betamethasone exposure is associated with lower ANG-(1–7) and increased ACE in the CSF of adult sheep

Marshall

Shaltout

Pirro

et al. 2013

American Journal of Physiology-Regulatory, Integrative and Comp

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Antenatal betamethasone (BM) therapy accelerates lung development in preterm infants but may induce early programming events with long-term cardiovascular consequences. To elucidate these events, we developed a model of programming whereby pregnant ewes are administered BM (2 doses of 0.17 mg/kg) or vehicle at the 80th day of gestation and offspring are delivered at term. BM-exposed (BMX) offspring develop elevated blood pressure; decreased baroreflex sensitivity; and alterations in the circulating, renal, and brain renin-angiotensin systems (RAS) by 6 mo of age. We compared components of the choroid plexus fourth ventricle (ChP4) and cerebral spinal fluid (CSF) RAS between control and BMX male offspring at 6 mo of age. In the choroid plexus, high-molecular-weight renin protein and ANG I-intact angiotensinogen were unchanged between BMX and control animals. Angiotensin-converting enzyme 2 (ACE2) activity was threefold higher than either neprilysin (NEP) or angiotensin 1-converting enzyme (ACE) in control and BMX animals. Moreover, all three enzymes were equally enriched by approximately 2.5-fold in ChP4 brush-border membrane preparations. CSF ANG-(1-7) levels were significantly lower in BMX animals (351.8 ± 76.8 vs. 77.5 ± 29.7 fmol/mg; P < 0.05) and ACE activity was significantly higher (6.6 ± 0.5 vs. 8.9 ± 0.5 fmol·min(-1)·ml(-1); P < 0.05), whereas ACE2 and NEP activities were below measurable limits. A thiol-sensitive peptidase contributed to the majority of ANG-(1-7) metabolism in the CSF, with higher activity in BMX animals. We conclude that in utero BM exposure alters CSF but not ChP RAS components, resulting in lower ANG-(1-7) levels in exposed animals.

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Section: Control Bmxmentioning

confidence: 59%

Antenatal betamethasone exposure is associated with lower ANG-(1–7) and increased ACE in the CSF of adult sheep

Marshall

Shaltout

Pirro

et al. 2013

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Studies by Crackower et al (7) using three different models of hypertension have shown an inverse relationship between ACE2 mRNA/protein levels and blood pressure. Additionally, since ACE and ACE2 are involved in generating and/or degrading the bioactive peptides of the RAS, levels of these peptidases predicted the occurrence of vasoconstriction over dilatation or the dominance of pathophysiological stimuli over beneficial conditions (6,37). Analysis of angiotensin fragments suggested that greater expression of ACE or a lower expression of ACE2 might have resulted in lowering of Ang (1-7) and increasing of ANG II in the HS-fed obese rats.…”

Section: Discussionmentioning

confidence: 94%

High Na intake increases renal angiotensin II levels and reduces expression of the ACE2-AT₂R-MasR axis in obese Zucker rats

Samuel

Ali

Sabuhi

et al. 2012

American Journal of Physiology-Renal Physiology

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High sodium intake is known to regulate the renal renin-angiotensin system (RAS) and is a risk factor for the pathogenesis of obesity-related hypertension. The complex nature of the RAS reveals that its various components may have opposing effects on natriuresis and blood pressure regulation. We hypothesized that high sodium intake differentially regulates and shifts a balance between opposing components of the renal RAS, namely, angiotensin-converting enzyme (ACE)-ANG II-type 1 ANG II receptor (AT(1)R) vs. AT(2)-ACE2-angiotensinogen (Ang) (1-7)-Mas receptor (MasR), in obesity. In the present study, we evaluated protein and/or mRNA expression of angiotensinogen, renin, AT(1A/B)R, ACE, AT(2)R, ACE2, and MasR in the kidney cortex following 2 wk of a 8% high-sodium (HS) diet in lean and obese Zucker rats. The expression data showed that the relative expression pattern of ACE and AT(1B)R increased, renin decreased, and ACE2, AT(2)R, and MasR remained unaltered in HS-fed lean rats. On the other hand, HS intake in obese rats caused an increase in the cortical expression of ACE, a decrease in ACE2, AT(2)R, and MasR, and no changes in renin and AT(1)R. The cortical levels of ANG II increased by threefold in obese rats on HS compared with obese rats on normal salt (NS), which was not different than in lean rats. The HS intake elevated mean arterial pressure in obese rats (27 mmHg) more than in lean rats (16 mmHg). This study suggests that HS intake causes a pronounced increase in ANG II levels and a reduction in the expression of the ACE2-AT(2)R-MasR axis in the kidney cortex of obese rats. We conclude that such changes may lead to the potentially unopposed function of AT(1)R, with its various cellular and physiological roles, including the contribution to the pathogenesis of obesity-related hypertension.

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“…Activation of the AT2R provides many opposing effects such as vasodilation, hypotension, apoptosis, antihypertrophic and inhibition of the AT1R [110]. There is a great deal of complexity in the RAS pathway, including numerous factors and receptors that participate in the pathway such as ACE2, Ang(1–7) and Ang(1–12) [111,112]. However, the AT1R and AT2R are the major contributors in transduction of extracellular signals to elicit the effects of Ang II.…”

Section: Interaction Between Mirnas and The Ras Related To Ir Injurymentioning

confidence: 99%

Differential expression of microRNAs in ischemic heart disease

Song

Paradis

Shin

et al. 2015

Drug Discovery Today

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Recent studies provide evidence that ischemic preconditioning (IP) and ischemia/reperfusion (IR) injury lead to altered expression of microRNAs (miRNAs) that affect the survival and recovery of cardiomyocytes. These endogenous ~22-nucleotide noncoding RNAs negatively regulate gene expression via degradation and translational inhibition of their target mRNAs. miRNAs are involved in differentiation, proliferation, electrical conduction, angiogenesis and apoptosis. These pathways can lead to physiological and pathological adaptations. This review intends to explore several facets of miRNA expression and the underlying mechanisms involved in IR injury, as well as IP as a cardioprotective strategy. In addition, we will investigate miRNA interaction with the renin–angiotensin system and the potential use of miRNAs in developing sensitive biomarkers for cardiovascular disease.

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Angiotensin-converting enzymes and drug discovery in cardiovascular diseases

Cited by 57 publications

References 102 publications

Antenatal betamethasone exposure is associated with lower ANG-(1–7) and increased ACE in the CSF of adult sheep

Antenatal betamethasone exposure is associated with lower ANG-(1–7) and increased ACE in the CSF of adult sheep

High Na intake increases renal angiotensin II levels and reduces expression of the ACE2-AT₂R-MasR axis in obese Zucker rats

Differential expression of microRNAs in ischemic heart disease

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Angiotensin-converting enzymes and drug discovery in cardiovascular diseases

Cited by 57 publications

References 102 publications

Antenatal betamethasone exposure is associated with lower ANG-(1–7) and increased ACE in the CSF of adult sheep

Antenatal betamethasone exposure is associated with lower ANG-(1–7) and increased ACE in the CSF of adult sheep

High Na intake increases renal angiotensin II levels and reduces expression of the ACE2-AT2R-MasR axis in obese Zucker rats

Differential expression of microRNAs in ischemic heart disease

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High Na intake increases renal angiotensin II levels and reduces expression of the ACE2-AT₂R-MasR axis in obese Zucker rats