The role of locally expressed angiotensin converting enzyme in cardiac remodeling after myocardial infarction in mice

Aartsen, Wendy M.; Schuijt, Martin P; Danser, A.H. Jan; Daemen, M. J. A. P.; Smits, J. F. M.

doi:10.1016/s0008-6363(02)00516-3

Cited by 13 publications

(15 citation statements)

References 42 publications

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“…In the heart, hypoxic conditions induce ATP release [35, 36]. Functionally, released ATP has been involved in inotropy and hypertrophy of cardiomyocytes [38], and, as more recently demonstrated, in myocardial cell death (our previous data [18] and the present results). All these effects are likely mediated by the activation of specific P2 receptors on either cardiomyocytes or fibroblasts.…”

Section: Discussionsupporting

confidence: 82%

Opposite effects of uracil and adenine nucleotides on the survival of murine cardiomyocytes

Mazzola

Amoruso

Beltrami

et al. 2007

J Cellular Molecular Medi

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We previously showed that the human heart expresses all known P2X and P2Y receptors activated by extra-cellular adenine or uracil nucleotides. Despite evidence that, both in humans and rodents, plasma levels of ATP and UTP markedly increase during myocardial infarction, the differential effects mediated by the various adenine- and uracil-preferring myocardial P2 receptors are still largely unknown. Here, we studied the effects of adenine and uracil nucleotides on murine HL-1 cardiomyocytes. RT-PCR analysis showed that HL-1 cardiomyocytes express all known P2X receptors (except for P2X2), as well as the P2Y2,4,6,14 subtypes. Exposure of cardiomyocytes to adenine nucleotides (ATP, ADP or BzATP) induced apoptosis and necrosis, as determined by flow-cytometry. Cell death was exacerbated by tumour necrosis factor (TNF)-α, a cytokine implicated in chronic heart failure progression. Conversely, uracil nucleotides (UTP, UDP and UDPglucose) had no effect ‘per se’, but fully counteracted the deleterious effects induced by adenine nucleotides and TNF-α, even if added to cardiomyocytes after beginning exposure to these cell death-inducing agents. Thus, exposure of cardiomyocytes to elevated concentrations of ATP or ADP in the presence of TNF-α contributes to cell death, an effect which is counteracted by uracil-preferring P2 receptors. Cardiomyocytes do not need to be ‘primed’ by uracil nucleotides to become insensitive to adenine nucleotides-induced death, suggesting the existence of a possible ‘therapeutic’ window for uracil nucleotides-mediated protection. Thus, release of UTP during cardiac ischaemia and in chronic heart failure may protect against myocardial damage, setting the basis for developing novel cardioprotective agents that specifically target uracil-preferring P2Y receptors.

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Section: Discussionsupporting

confidence: 82%

Opposite effects of uracil and adenine nucleotides on the survival of murine cardiomyocytes

Mazzola

Amoruso

Beltrami

et al. 2007

J Cellular Molecular Medi

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“…It is known that there are tissue-bound and soluble forms of ACE, 22 but it is not known whether there is a soluble form of the enzyme inside the cell. Recently, [22][23][24] evidence was provided that intracellular administration of enalaprilat to 2-month-old cardiomyopathic hamsters in which ACE activity is not enhanced did not change the cell coupling, whereas the same amount of enalaprilat increased the junctional conductance by 72Ϯ6.2% in 6-month-old cardiomyopathic hamsters in which ACE activity is appreciably increased. These findings and the present observations support the notion that endogenous Ang II contributes to the modulation of I Ca and cell coupling in the failing heart.…”

Section: Mello and Monterrubiomentioning

confidence: 99%

Intracellular and Extracellular Angiotensin II Enhance the L-Type Calcium Current in the Failing Heart

Mello

Monterrubio

2004

Hypertension

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Abstract-The influence of intracellular and extracellular angiotensin II (Ang II) on the L-type calcium current of cardiomyocytes isolated from cardiomyopathic hamsters was investigated. The results indicated that Ang II (10 Ϫ8 mmol/L), added to the bath, increased the peak inward calcium current (I Ca ) density by 37Ϯ3.4% (PϽ0.05), an effect that depends on the activation of protein kinase C. Intracellular administration of the same dose of Ang II (10 Ϫ8 mmol/L) also elicited an increase of peak I Ca density but enhanced the rate of I Ca inactivation, an effect not seen with extracellular Ang II. Moreover, in control animals, no change in the rate of I Ca inactivation was seen with intracellular Ang II. Thapsigargin (1 mol/L), a potent inhibitor of sarcoplasmic reticulum (SR) ATPase, which depletes the SR, decreased the rate of I Ca inactivation elicited by intracellular Ang II, although the cytoplasmic calcium concentration was highly buffered with 10 mmol/L EGTA. These findings might indicate that intracellular Ang II releases calcium from the SR and inactivates I Ca . The effect of intracellular Ang II on peak I Ca was not altered by extracellular losartan (10 Ϫ7 mmol/L), supporting the notion that the peptide acted intracellularly. Other studies showed that intracellular Ang I administration (10 Ϫ8 mmol/L) enhanced the peak I Ca density and the rate of I Ca inactivation, an effect that was reduced by intracellular enalaprilat (10 Ϫ8 mmol/L). Moreover, intracellular enalaprilat by itself reduced the peak I Ca density. These observations might indicate that endogenous Ang II is contributing to I Ca modulation in the failing heart. Key Words: angiotensin Ⅲ heart failure Ⅲ calcium current T he concept of a cardiac renin-angiotensin system 1 gained support with the demonstration that: (1) angiotensin I (Ang I) is converted to Ang II in the isolated and perfused heart; 2 (2) the angiotensin-converting enzyme (ACE) has been found around the nucleus of heart cells in culture 3 ; and (3) ACE inhibitors prevent cardiac remodeling, an effect independent of the change in blood pressure. 4 However, in normal heart, renin mRNA levels 5 and renin content are negligible in nephrectomized rats. 6 Moreover, no renin is released from the isolated and perfused rat heart, 7 which suggests that cardiac renin is attributable to its uptake from plasma. However, under some conditions, such as stretch, renin gene expression is enhanced, 8 and overexpression of angiotensinogen gene in normal mice leads to hypertrophy of the right and left ventricles and to an increase of Ang II levels in both ventricles without any change in arterial blood pressure. 9,10 Furthermore, a second renin gene transcript that may code for intracellular renin because it lacks the coding zone of the secretory signal peptide is upregulated in the left ventricle after myocardial infarction. 11 Moreover, cardiac angiotensinogen is upregulated after myocardial infarction. 12 These observations support the notion that renin and Ang II can be formed inside the hear...

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“…We induced MI in 24 Swiss mice (age 10–12 weeks) using our study protocol described previously 19 . Briefly, xylazine (5 mg/kg s.c.) and ketamine (1 mg/kg i.m.)…”

Section: Methodsmentioning

confidence: 99%

Myocardial and Serum Galectin-3 Expression Dynamics Marks Post-Myocardial Infarction Cardiac Remodelling

Sharma

Mosleh

Chaudhari

et al. 2017

Heart, Lung and Circulation

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Background Acute myocardial infarction (MI) causes significant changes in cardiac morphology and function. Galectin-3 is a novel and potentially therapeutically important mediator of cardiac remodelling. Myocardial and serum galectin-3 expression dynamics in response to the early cardiovascular outcomes after acute MI are not fully elucidated. Methods We first performed a comprehensive longitudinal microarray analyses in mice after acute MI. We then measured the serum levels of galectin-3 in a translational porcine model of coronary microembolism-induced post-ischaemic cardiac remodelling. We validated our pre-clinical studies in humans by measuring serum galectin-3 levels of 52 patients with acute ST-elevation MI (STEMI) and 11 healthy controls. We analysed galectin-3 data in relation to the development of major adverse cardiovascular outcomes (MACO). Results Of the 9,753 genes profiled at infarcted and remote myocardium at eight different time points, dynamic myocardial overexpression of galectin-3 mRNA was detected. In a pig model of diffuse myocardial damage and cardiac remodelling, galectin-3 localised to the areas of tissue damage and myocardial fibrosis, with proportionate increase of their serum galectin-3 expression levels. In humans, increased serum galectin-3 level was associated with in-hospital MACO. Conclusions In this translational study, we demonstrated that galectin-3 is dynamically overexpressed in response to acute MI-induced cardiac remodelling. Elevated galectin-3 levels are associated with the development of in-hospital MACO.

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The role of locally expressed angiotensin converting enzyme in cardiac remodeling after myocardial infarction in mice

Abstract: These results suggest that the structural adaptations of the heart that follow MI are independent of t-ACE. However, the presence of t-ACE is necessary for maintenance of cardiac function.

Cited by 13 publications

References 42 publications

Opposite effects of uracil and adenine nucleotides on the survival of murine cardiomyocytes

Opposite effects of uracil and adenine nucleotides on the survival of murine cardiomyocytes

Intracellular and Extracellular Angiotensin II Enhance the L-Type Calcium Current in the Failing Heart

Myocardial and Serum Galectin-3 Expression Dynamics Marks Post-Myocardial Infarction Cardiac Remodelling

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