Mice expressing ACE only in the heart show that increased cardiac angiotensin II is not associated with cardiac hypertrophy.
01 Feb 2008-American Journal of Physiology-heart and Circulatory Physiology (American Physiological Society)-Vol. 294, Iss: 2
TL;DR: The data suggest that a moderate increase of local angiotensin II production in the heart does not produce cardiac dysfunction, at least under basal conditions, and that, in response to aortic banding, cardiac hypertrophy is not augmented by a twofold increase of cardiac angiotENSin II.
Abstract: In the heart, angiotensin II has been suggested to regulate cardiac remodeling and promote cardiac hypertrophy. To examine this, we studied compound heterozygous mice, called angiotensin-converting enzyme (ACE) 1/8, in which one ACE allele is null, whereas the other ACE allele (the 8 allele) targets expression to the heart. In this model, cardiac ACE levels are about 15 times those of wild-type mice, and ACE expression is reduced or eliminated in other tissues. ACE 1/8 mice have 58% the cardiac ACE of a previous model, called ACE 8/8, but both ACE 1/8 and ACE 8/8 mice have ventricular angiotensin II levels about twofold those of wild-type controls. Despite equivalent levels of cardiac angiotensin II, ACE 1/8 mice do not develop the marked atrial enlargement or the conduction defects previously reported in the ACE 8/8 mice. Six-month-old ACE 1/8 mice have normal cardiac function, as determined by echocardiography and left ventricular catheterization, despite the elevated levels of angiotensin II. ACE 1/8 mice also have normal levels of connexin 43. Both wild-type and ACE 1/8 mice develop similar degrees of cardiac hypertrophy after aortic banding. These data suggest that a moderate increase of local angiotensin II production in the heart does not produce cardiac dysfunction, at least under basal conditions, and that, in response to aortic banding, cardiac hypertrophy is not augmented by a twofold increase of cardiac angiotensin II.
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TL;DR: Knowing the structural differences between the two ACE domains should allow clinicians to envision new therapies for diseases not currently treated with ACE inhibitors, and these reagents will undoubtedly be powerful tools for probing the physiologic actions of each ACE domain.
Abstract: Angiotensin-converting enzyme (ACE) is a zinc-dependent peptidase responsible for converting angiotensin I into the vasoconstrictor angiotensin II. However, ACE is a relatively nonspecific peptidase that is capable of cleaving a wide range of substrates. Because of this, ACE and its peptide substrates and products affect many physiologic processes, including blood pressure control, hematopoiesis, reproduction, renal development, renal function, and the immune response. The defining feature of ACE is that it is composed of two homologous and independently catalytic domains, the result of an ancient gene duplication, and ACE-like genes are widely distributed in nature. The two ACE catalytic domains contribute to the wide substrate diversity of ACE and, by extension, the physiologic impact of the enzyme. Several studies suggest that the two catalytic domains have different biologic functions. Recently, the X-ray crystal structure of ACE has elucidated some of the structural differences between the two ACE domains. This is important now that ACE domain-specific inhibitors have been synthesized and characterized. Once widely available, these reagents will undoubtedly be powerful tools for probing the physiologic actions of each ACE domain. In turn, this knowledge should allow clinicians to envision new therapies for diseases not currently treated with ACE inhibitors.
247 citations
Cites background from "Mice expressing ACE only in the hea..."
...However, others have shown that local increase of angiotensin II production in the heart does not produce cardiac hypertrophy (Xiao et al., 2008), and that AT1 receptor exclusively in the kidneys is sufficient to induce hypertension and cardiac hypertrophy (Crowley et al., 2006)....
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...ACE activity in the testes increased between 40 and 50 days after birth, when mature sperm are first present....
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TL;DR: Cardiac oxidation, independently of vascular changes, can lead to uncoupled cardiac NOS and diastolic dysfunction, and BH4 may represent a possible treatment for diastolics dysfunction.
Abstract: Background— Heart failure with preserved ejection fraction is 1 consequence of hypertension and is caused by impaired cardiac diastolic relaxation. Nitric oxide (NO) is a known modulator of cardiac relaxation. Hypertension can lead to a reduction in vascular NO, in part because NO synthase (NOS) becomes uncoupled when oxidative depletion of its cofactor tetrahydrobiopterin (BH4) occurs. Similar events may occur in the heart that lead to uncoupled NOS and diastolic dysfunction. Methods and Results— In a hypertensive mouse model, diastolic dysfunction was accompanied by cardiac oxidation, a reduction in cardiac BH4, and uncoupled NOS. Compared with sham-operated animals, male mice with unilateral nephrectomy, with subcutaneous implantation of a controlled-release deoxycorticosterone acetate pellet, and given 1% saline to drink were mildly hypertensive and had diastolic dysfunction in the absence of systolic dysfunction or cardiac hypertrophy. The hypertensive mouse hearts showed increased oxidized biopterin...
235 citations
TL;DR: Findings are consistent with a model in which exercise may induce left ventricular hypertrophy, at least in part, altering the expression of specific microRNAs targeting renin-angiotensin system genes, which might provide the additional aerobic capacity required by the exercised heart.
Abstract: Aerobic exercise training leads to a physiological, nonpathological left ventricular hypertrophy; however, the underlying biochemical and molecular mechanisms of physiological left ventricular hypertrophy are unknown. The role of microRNAs regulating the classic and the novel cardiac renin-angiotensin (Ang) system was studied in trained rats assigned to 3 groups: (1) sedentary; (2) swimming trained with protocol 1 (T1, moderate-volume training); and (3) protocol 2 (T2, high-volume training). Cardiac Ang I levels, Ang-converting enzyme (ACE) activity, and protein expression, as well as Ang II levels, were lower in T1 and T2; however, Ang II type 1 receptor mRNA levels (69% in T1 and 99% in T2) and protein expression (240% in T1 and 300% in T2) increased after training. Ang II type 2 receptor mRNA levels (220%) and protein expression (332%) were shown to be increased in T2. In addition, T1 and T2 were shown to increase ACE2 activity and protein expression and Ang (1-7) levels in the heart. Exercise increased microRNA-27a and 27b, targeting ACE and decreasing microRNA-143 targeting ACE2 in the heart. Left ventricular hypertrophy induced by aerobic training involves microRNA regulation and an increase in cardiac Ang II type 1 receptor without the participation of Ang II. Parallel to this, an increase in ACE2, Ang (1-7), and Ang II type 2 receptor in the heart by exercise suggests that this nonclassic cardiac renin-angiotensin system counteracts the classic cardiac renin-angiotensin system. These findings are consistent with a model in which exercise may induce left ventricular hypertrophy, at least in part, altering the expression of specific microRNAs targeting renin-angiotensin system genes. Together these effects might provide the additional aerobic capacity required by the exercised heart.
196 citations
TL;DR: Results indicate that activation of Gα12/13 in cardiomyocytes by the extracellular nucleotides‐stimulated P2Y6 receptor triggers fibrosis in pressure overload‐induced cardiac fibrosis, which works as an upstream mediator of the signalling pathway between Ang II and TGF‐β.
Abstract: Cardiac fibrosis, characterized by excessive deposition of extracellular matrix proteins, is one of the causes of heart failure, and it contributes to the impairment of cardiac function. Fibrosis of various tissues, including the heart, is believed to be regulated by the signalling pathway of angiotensin II (Ang II) and transforming growth factor (TGF)-β. Transgenic expression of inhibitory polypeptides of the heterotrimeric G12 family G protein (Gα12/13) in cardiomyocytes suppressed pressure overload-induced fibrosis without affecting hypertrophy. The expression of fibrogenic genes (TGF-β, connective tissue growth factor, and periostin) and Ang-converting enzyme (ACE) was suppressed by the functional inhibition of Gα12/13. The expression of these fibrogenic genes through Gα12/13 by mechanical stretch was initiated by ATP and UDP released from cardiac myocytes through pannexin hemichannels. Inhibition of G-protein-coupled P2Y6 receptors suppressed the expression of ACE, fibrogenic genes, and cardiac fibrosis. These results indicate that activation of Gα12/13 in cardiomyocytes by the extracellular nucleotides-stimulated P2Y6 receptor triggers fibrosis in pressure overload-induced cardiac fibrosis, which works as an upstream mediator of the signalling pathway between Ang II and TGF-β.
164 citations
Cites result from "Mice expressing ACE only in the hea..."
...However, our data are consistent with the results of Xiao et al. (2008), which show that an increase in ACE expression does not augment pres- sure overload-induced cardiac hypertrophy in mice....
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TL;DR: It is shown that the angiotensin II type 1 (AT1) receptor is locally activated in pathological and physiological cardiac hypertrophy, although with exercise training it can be stimulated independently of the involvement of angiotENSin II.
Abstract: Among the molecular, biochemical and cellular processes that orchestrate the development of the different phenotypes of cardiac hypertrophy in response to physiological stimuli or pathological insults, the specific contribution of exercise training has recently become appreciated. Physiological cardiac hypertrophy involves complex cardiac remodeling that occurs as an adaptive response to static or dynamic chronic exercise, but the stimuli and molecular mechanisms underlying transduction of the hemodynamic overload into myocardial growth are poorly understood. This review summarizes the physiological stimuli that induce concentric and eccentric physiological hypertrophy, and discusses the molecular mechanisms, sarcomeric organization, and signaling pathway involved, also showing that the cardiac markers of pathological hypertrophy (atrial natriuretic factor, β-myosin heavy chain and α-skeletal actin) are not increased. There is no fibrosis and no cardiac dysfunction in eccentric or concentric hypertrophy induced by exercise training. Therefore, the renin-angiotensin system has been implicated as one of the regulatory mechanisms for the control of cardiac function and structure. Here, we show that the angiotensin II type 1 (AT1) receptor is locally activated in pathological and physiological cardiac hypertrophy, although with exercise training it can be stimulated independently of the involvement of angiotensin II. Recently, microRNAs (miRs) have been investigated as a possible therapeutic approach since they regulate the translation of the target mRNAs involved in cardiac hypertrophy; however, miRs in relation to physiological hypertrophy have not been extensively investigated. We summarize here profiling studies that have examined miRs in pathological and physiological cardiac hypertrophy. An understanding of physiological cardiac remodeling may provide a strategy to improve ventricular function in cardiac dysfunction.
87 citations
Cites background from "Mice expressing ACE only in the hea..."
...(32) reported that in mice expressing ACE only in the heart the increase in cardiac Ang II was not associated with cardiac hypertrophy, indicating that the increase of cardiac Ang II was not sufficient to induce hypertrophy....
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References
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TL;DR: Total mortality and hospitalization for congestive heart failure are significantly reduced by ACE inhibitors with consistent effects in a broad range of patients.
Abstract: Objective. —To evaluate the effect of angiotensin-converting enzyme (ACE) inhibitors on mortality and morbidity in patients with symptomatic congestive heart failure. Data Sources and Study Selection. —Data were obtained for all completed, published or unpublished, randomized, placebo-controlled trials of ACE inhibitors that were at least 8 weeks in duration and had determined total mortality by intention to treat, regardless of sample size. Trials were identified based on literature review and correspondence with investigators and pharmaceutical firms. Data Extraction. —Using standard tables, data were extracted by one author and confirmed where necessary by the other author or the principal investigator of the trial. Unpublished data were obtained by direct correspondence with the principal investigator of each study or pharmaceutical firm. Data Synthesis. —The data for each outcome were combined using the Yusuf-Peto adaptation of the Mantel-Haenszel method. Overall, there was a statistically significant reduction in total mortality (odds ratio [OR], 0.77; 95% confidence interval [CI], 0.67 to 0.88;P Conclusions. —Total mortality and hospitalization for congestive heart failure are significantly reduced by ACE inhibitors with consistent effects in a broad range of patients. (JAMA. 1995;273:1450-1456)
1,822 citations
TL;DR: These genetic data for ACE2 show that it is an essential regulator of heart function in vivo and targeted disruption of ACE2 in mice results in a severe cardiac contractility defect, increased angiotensin II levels, and upregulation of hypoxia-induced genes in the heart.
Abstract: Cardiovascular diseases are predicted to be the most common cause of death worldwide by 2020. Here we show that angiotensin-converting enzyme 2 (ace2) maps to a defined quantitative trait locus (QTL) on the X chromosome in three different rat models of hypertension. In all hypertensive rat strains, ACE2 messenger RNA and protein expression were markedly reduced, suggesting that ace2 is a candidate gene for this QTL. Targeted disruption of ACE2 in mice results in a severe cardiac contractility defect, increased angiotensin II levels, and upregulation of hypoxia-induced genes in the heart. Genetic ablation of ACE on an ACE2 mutant background completely rescues the cardiac phenotype. But disruption of ACER, a Drosophila ACE2 homologue, results in a severe defect of heart morphogenesis. These genetic data for ACE2 show that it is an essential regulator of heart function in vivo.
1,630 citations
"Mice expressing ACE only in the hea..." refers background in this paper
...Previous analysis of ACE2 knockout mice showed cardiac deterioration appearing at 6 mo of age (5)....
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TL;DR: The phenotypic changes of cardiac cells in response to Ang II in vitro closely mimic those of growth factor response in vitro and of load-induced hypertrophy in vivo, and all biological effects of Ang II examined here are mediated primarily by the AT1 receptors.
Abstract: Increasing evidence suggests that angiotensin II (Ang II) may act as a growth factor for the heart. However, direct effects of Ang II on mammalian cardiac cells (myocytes and nonmyocytes), independent of secondary hemodynamic and neurohumoral effects, have not been well characterized. Therefore, we analyzed the molecular phenotype of cultured cardiac cells from neonatal rats in response to Ang II. In addition, we examined the effects of selective Ang II receptor subtype antagonists in mediating the biological effects of Ang II. In myocyte culture, Ang II caused an increase in protein synthesis without changing the rate of DNA synthesis. In contrast, Ang II induced increases in protein synthesis, DNA synthesis, and cell number in nonmyocyte cultures (mostly cardiac fibroblasts). The Ang II-induced hypertrophic response of myocytes and mitogenic response of fibroblasts were mediated primarily by the AT1 receptor. Ang II caused a rapid induction of many immediate-early genes (c-fos, c-jun, jun B, Egr-1, and c-myc) in myocyte and nonmyocyte cultures. Ang II induced "late" markers for cardiac hypertrophy, skeletal alpha-actin and atrial natriuretic factor expression, within 6 hours in myocytes. Ang II also caused upregulation of the angiotensinogen gene and transforming growth factor-beta 1 gene within 6 hours. Induction of immediate-early genes, late genes, and growth factor genes by Ang II was fully blocked by an AT1 receptor antagonist but not by an AT2 receptor antagonist. These results indicate that: (1) Ang II causes hypertrophy of cardiac myocytes and mitogenesis of cardiac fibroblasts, (2) the phenotypic changes of cardiac cells in response to Ang II in vitro closely mimic those of growth factor response in vitro and of load-induced hypertrophy in vivo, (3) all biological effects of Ang II examined here are mediated primarily by the AT1 receptor subtype, and (4) Ang II may initiate a positive-feedback regulation of cardiac hypertrophic response by inducing the angiotensinogen gene and transforming growth factor-beta 1 gene.
1,413 citations
"Mice expressing ACE only in the hea..." refers background in this paper
...A direct role of angiotensin II is supported by in vitro studies showing that angiotensin II can stimulate the growth of cardiomyocytes in cell culture (9, 24, 25)....
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...In vitro studies also suggested that angiotensin II directly stimulated cardiomyocyte growth (9, 24, 25)....
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TL;DR: The studies show that AII is a potent hypertrophic agent but has no detectable mitogenic activity in cultured rat aortic smooth muscle cells and describe an in vitro model that should be extremely valuable in exploring the cellular controls of smooth muscle cell hypertrophy.
Abstract: We have explored the hypothesis that contractile agonists are important regulators of smooth muscle cell growth by examining the effects of one potent contractile agonist, angiotensin II (AII), on both cell proliferation and cellular hypertrophy. AII neither stimulated proliferation of cells made quiescent in a defined serum-free media nor augmented cell proliferation induced by serum or platelet-derived growth factor. However, AII did induce cellular hypertrophy of postconfluent quiescent cultures following 4 days of treatment, increasing smooth muscle cell protein content by 20% as compared with vehicle-treated controls. AII-induced hypertrophy was maximal at 1 microM, had an ED50 of 5 nM, and was blocked by the specific AII receptor antagonist Sar1,Ile8 AII. The cellular hypertrophy was due to an increase in protein synthesis, which was elevated within 6-9 hours following AII treatment, while no changes in protein degradation were apparent. AII was even more effective in inducing hypertrophy of subconfluent cultures, causing a 38% increase in protein content after 4 days of treatment (1 microM) and showing a maximal response at concentrations as low as 0.1 nM. Interestingly, in subconfluent cultures, AII treatment (1 microM, 4 days) was associated with a 50% increase in the fraction of cells with 4C DNA content with the virtual absence of cells in S-phase of the cell cycle, consistent with either arrest of cells in the G2 phase of the cell cycle or development of tetraploidy.(ABSTRACT TRUNCATED AT 250 WORDS)
1,093 citations
"Mice expressing ACE only in the hea..." refers background in this paper
...A direct role of angiotensin II is supported by in vitro studies showing that angiotensin II can stimulate the growth of cardiomyocytes in cell culture (9, 24, 25)....
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...In vitro studies also suggested that angiotensin II directly stimulated cardiomyocyte growth (9, 24, 25)....
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Journal Article•
TL;DR: ACE-deficient animals demonstrate the role of this enzyme in systemic blood pressure, renal development and function, and male fertility as well as the importance of testis ACE in male fertility.
446 citations
"Mice expressing ACE only in the hea..." refers background in this paper
...Both these models were previously described and contain mutations produced by targeted homologous recombination in embryonic stem cells (7, 28)....
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...The elimination of ACE in genetically engineered mice leads to a marked reduction of blood pressure, underlining the vital role of ACE in the normal control of blood pressure (7)....
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