Right ventricular angiotensin converting enzyme activity and expression is increased during hypoxic pulmonary hypertension

Morrell, Nicholas W.; Danilov, Sergei M.; Satyan, Krishna B; Morris, Kenneth G.; Stenmark, Kurt R.

doi:10.1016/s0008-6363(97)00049-7

Cited by 68 publications

(41 citation statements)

References 33 publications

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“…Two weeks of HH exposure increased mean pulmonary arterial pressure and total pulmonary resistance, confirming PH. In addition, 2 wk of HH significantly decreased stroke volume and increased RV and right atrial pressures (summarized in Table 1), confirming concomitant RV dysfunction, as previously observed in this model (24,28).…”

Section: Resultssupporting

confidence: 87%

Mitochondrial integrity in a neonatal bovine model of right ventricular dysfunction

Bruns

Brown

Stenmark

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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(LV) failure, yet the mechanisms of RV failure are poorly understood. Recent studies suggest cardiac metabolism is altered in RV failure in pulmonary hypertension (PH). Accordingly, we assessed mitochondrial content, dynamics, and function in hearts from neonatal calves exposed to hypobaric hypoxia (HH). This model develops severe PH with concomitant RV hypertrophy, dilation, and dysfunction. After 2 wk of HH, pieces of RV and LV were obtained along with samples from age-matched controls. Comparison with control assesses the effect of hypoxia, whereas comparison between the LV and RV in HH assesses the additional impact of RV overload. Mitochondrial DNA was unchanged in HH, as was mitochondrial content as assessed by electron microscopy. Immunoblotting for electron transport chain subunits revealed a small increase in mitochondrial content in HH in both ventricles. Mitochondrial dynamics were largely unchanged. Activity of individual respiratory chain complexes was reduced (complex I) or unchanged (complex V) in HH. Key enzymes in the glycolysis pathway were upregulated in both HH ventricles, alongside upregulation of hypoxia-inducible factor-1␣ protein. Importantly, none of the changes in expression or activity were different between ventricles, suggesting the changes are in response to HH and not RV overload. Upregulation of glycolytic modulators without chamber-specific mitochondrial dysfunction suggests that mitochondrial capacity and activity are maintained at the onset of PH, and the early RV dysfunction in this model results from mechanisms independent of the mitochondria. pulmonary hypertension; right ventricle; cardiac; mitochondria HEART FAILURE (HF) is characterized by an inability of the ventricles to pump sufficient blood flow to working tissue. Regardless of upstream signaling, the failing heart cannot generate sufficient myofilament force to sustain adequate perfusion pressures. Multiple hypotheses have been put forward to explain this contractile deficit, including myofilament protein dysfunction. However, we have shown in a large animal model of right ventricular (RV) dysfunction that myofilament protein properties are not likely to be solely responsible for the contractile deficit, since isolated skinned cardiac myocytes from hypobaric hypoxia (HH) calves produce similar forces as skinned myocytes from control calves, despite significant organ-level dysfunction (42). Therefore, additional mechanisms must explain the contractile dysfunction observed. Myofilament contraction requires a reliable energy source in the form of ATP for generation of force and maintenance of intracellular calcium gradients. Cardiac hypertrophy and HF are associated with metabolic dysregulation and chronic energy deficiency (15, 29), suggesting energy deficits in the failing heart are associated with and may contribute to the contractile dysfunction. Although a number of metabolic changes have been examined, the outcomes in a number of animal models of ventricular failure have been discordant, with some models showing...

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Section: Resultssupporting

confidence: 87%

Mitochondrial integrity in a neonatal bovine model of right ventricular dysfunction

Bruns

Brown

Stenmark

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…2), indicating a stimulating effect of hypoxia on both AT 1 expression and receptor density in VSM cells. Chronic systemic hypoxia has been shown to activate RAS in a number of tissues, including the kidney, lung, heart, and pancreas (11,29,34). Leung et al (24) also recently reported an upregulation of AT 1 receptor expression and function in the carotid body by isobaric hypoxia.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia and high glucose upregulate AT₁receptor expression and potentiate ANG II-induced proliferation in VSM cells

Sodhi¹,

Kanwar

Sahai³

2003

American Journal of Physiology-Heart and Circulatory Physiology

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We examined the effect of hypoxia and high glucose (HG) on ANG II type 1 (AT 1) receptor expression and proliferation in cultured vascular smooth muscle (VSM) cells. Exposure of quiescent cells to hypoxia in a serum-free DME-Ham's F-12 medium for 6-24 h induced a progressive increase in AT 1 mRNA expression. Exposure of cells to 24 h of hypoxia also resulted in a significant increase in ANG II receptor binding as assessed with 125 I-labeled ANG II. Treatment with ANG II (1 M) for 24 h under normoxic conditions caused an ϳ1.5-fold increase in both DNA synthesis and cell number, which was enhanced to ϳ3.0-fold under hypoxic conditions. An AT 1 receptor antagonist (losartan, 10 M) blocked the ANG II-induced increase in DNA synthesis under both normoxic and hypoxic conditions. Incubations in HG medium (25 mM) for 12-24 h under normoxic conditions induced an ϳ2.5-fold increase in AT 1 mRNA levels, which was markedly enhanced by hypoxia to ϳ5.5-fold at 12 h and ϳ8.5-fold at 24 h. ANG II under HG-normoxic conditions caused a complete downregulation of AT 1 expression, which was prevented by hypoxia. These results demonstrate an upregulation of AT 1 receptor expression by hypoxia and HG in cultured VSM cells and suggest a mechanism for enhanced ANG II-induced VSM cell proliferation and the development of atherosclerosis in diabetes. vascular smooth muscle cells; diabetes; chronic hypoxia; cell growth; angiotensin II receptor ARTERIAL WALL HYPOXIA and the associated vascular smooth muscle (VSM) cell proliferation have been implicated in the development of atherosclerosis (7, 23). Moreover, we recently reported (43) that hypoxia directly induces the proliferation of cultured rat aortic VSM cells. Others have shown that hypoxia is also mitogenic to cultured pulmonary artery smooth muscle and endothelial cells (12,13,25). Prevalence of tissue hypoxia and increased VSM cell proliferation is also reported in experimental models of diabetes and hypertension (1,10,28,35,40,45). Elevated glucose concentrations in medium have been shown to produce both hypertrophic and hyperplastic effects in cultured porcine aortic smooth muscle cells (32). We found (43, 44) that high medium glucose also induces the proliferation of cultured VSM cells as well as renal glomerular mesangial cells. In addition, hypoxia potentiates the effect of high medium glucose on the proliferation of both VSM and mesangial cells (43,44). Together, these results strongly suggest an important role for local hypoxia in accelerated VSM cell proliferation in diabetes. The mechanisms responsible for the accelerated VSM cell growth and progression into cardiovascular disease in diabetes remain to be clearly defined.Activation of the renin-angiotensin system (RAS) plays an important role in the pathogenesis of vascular complications of diabetes (16). The primary active component of the RAS, ANG II, causes hypertrophy, hyperplasia, and the deposition of extracellular matrix proteins in VSM cells (19,21,36,49). Interestingly, ANG II-induced proliferation of cultured rat ...

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“…Increased ACE activity and expression in the RV have been reported during chronic hypoxia (25). In addition, the benefit of ACE inhibitors and AT 1 receptor antagonists against the development of RV hypertrophy (13,14,26,32,41) point for an important role of ANG II in the process.…”

Section: Discussionmentioning

confidence: 99%

Cardiac modulations of ANG II receptor expression in rats with hypoxic pulmonary hypertension

Adamy

Oliviéro

Eddahibi

et al. 2002

American Journal of Physiology-Heart and Circulatory Physiology

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. Cardiac modulations of ANG II receptor expression in rats with hypoxic pulmonary hypertension. Am J Physiol Heart Circ Physiol 283: H733-H740, 2002. First published April 18, 2002 10.1152/ ajpheart.01088.2001.-Right ventricular myocardial hypertrophy during hypoxic pulmonary hypertension is associated with local renin-angiotensin system activation. The expression of angiotensin II type 1 (AT 1) and type 2 (AT2) receptors in this setting has never been investigated. We have therefore examined the chronic hypoxia pattern of AT 1 and AT2 expression in the right and left cardiac ventricles, using in situ binding and RT-PCR assays. Hypoxia produced right, but not left, ventricular hypertrophy after 7, 14, and 21 days, respectively. Hypoxia for 2 days was associated in each ventricle with a simultaneous and transient increase (P Ͻ 0.05) in AT1 binding and AT1 mRNA levels in the absence of any significant change in AT 2 expression level. Only after 14 days of hypoxia, AT 2 binding increased (P Ͻ 0.05) in the two ventricles, concomitantly with a right ventricular decrease (P Ͻ 0.05) in AT 2 mRNA. Along these data, AT1 and AT2 binding remained unchanged in both the left and hypertrophied right ventricles from rats treated with monocrotaline for 30 days. These results indicate that chronic hypoxia induces modulations of AT1 and AT2 receptors in both cardiac ventricles probably through direct and indirect mechanisms, respectively, which modulations may participate in myogenic (at the level of smooth or striated myocytes) rather than in the growth response of the heart to hypoxia. chronic hypoxia; heart ventricles; angiotensin II; AT1 and AT 2 receptor subtypes CHRONIC HYPOXIA-INDUCED pulmonary hypertension is characterized by an increased pulmonary vascular resistance due to pulmonary artery thickening that impedes ejection of blood by the cardiac right ventricle (RV) and leads to RV hypertrophy (1,20,21,33). Evidence that chronic hypoxia increases the plasma levels of renin (9), angiotensin-converting enzyme (ACE) (24), and angiotensin II (ANG II) (42) has stimulated interest in the contribution of the renin-angiotensin system to the hypoxia-induced cardiopulmonary changes. This hypothesis is supported by data from chronically hypoxic rats showing that ACE inhibitor treatment reduces pulmonary arterial pressure (5,14,26,27,34,41), pulmonary artery thickening (5, 26, 27, 41), and RV hypertrophy (14,26,32,41).Two pharmacologically distinct subtypes of receptors, designated as AT 1 and AT 2 , participate in regulating ANG II activity. Both have been described based on their affinity for selective receptor antagonists and their sensitivity to reducing agents (6). Whereas AT 1 mediates the vasoconstrictor and growth-promoting effects of ANG II, AT 2 has been suggested to mediate vasodilator effects and to exert antigrowth action within many cell types, including vascular smooth muscle cells, endothelial cells, cardiac fibroblasts, and myocytes (6,12,22,23). We have shown in the rat hypoxic lung that AT 1 and AT 2 receptor e...

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Right ventricular angiotensin converting enzyme activity and expression is increased during hypoxic pulmonary hypertension

Cited by 68 publications

References 33 publications

Mitochondrial integrity in a neonatal bovine model of right ventricular dysfunction

Mitochondrial integrity in a neonatal bovine model of right ventricular dysfunction

Hypoxia and high glucose upregulate AT₁receptor expression and potentiate ANG II-induced proliferation in VSM cells

Cardiac modulations of ANG II receptor expression in rats with hypoxic pulmonary hypertension

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Right ventricular angiotensin converting enzyme activity and expression is increased during hypoxic pulmonary hypertension

Cited by 68 publications

References 33 publications

Mitochondrial integrity in a neonatal bovine model of right ventricular dysfunction

Mitochondrial integrity in a neonatal bovine model of right ventricular dysfunction

Hypoxia and high glucose upregulate AT1receptor expression and potentiate ANG II-induced proliferation in VSM cells

Cardiac modulations of ANG II receptor expression in rats with hypoxic pulmonary hypertension

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Hypoxia and high glucose upregulate AT₁receptor expression and potentiate ANG II-induced proliferation in VSM cells