Hypoxia and acidosis impair cGMP synthesis in microvascular coronary endothelial cells

Agulló, Luís; Garcı́a-Dorado, David; Escalona, Noèlia; Inserte, Javier; Ruiz‐Meana, Marisol; Barrabés, José A.; Mirabet, Maribel; Pina, Pilar; Soler‐Soler, Jordi

doi:10.1152/ajpheart.01067.2001

Cited by 32 publications

(23 citation statements)

References 41 publications

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“…[16][17][18] Simulated ischemia severely depresses cGMP synthesis in microvascular endothelium through ATP depletion and acidosis, thereby reducing NO production. 19 Hypoxic ischemia induces a combination of hyperosmolarity and lactic acidosis which modify red blood cells. The erythrocyte membrane becomes more rigid with time, which contributes to the decreased erythrocyte deformability after AMI.…”

Section: (Iii) Fluids and Calcium Fluxmentioning

confidence: 99%

Coronary microvascular reperfusion injury and no-reflow in acute myocardial infarction

Kang

Yang

2007

CIM

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Purpose: To review (1) the mechanisms of coronary microvascular reperfusion injury, particularly in the relationships between microvascular endothelium dysfunction, microstructure damage, microemboli and no-reflow phenomena; (2) the no-reflow presentation and management at ischemia-reperfusion to suggest future direction for noreflow therapy in acute myocardial infarction. Sources: Original articles and reviews published between 1997 and 2007 and focusing on the no-reflow phenomenon in MEDLINE and PubMed. The search terms used were "no-reflow", "microvascular injury", "acute myocardial infarction" and "reperfusion injury". All papers identified were English-language, full text papers. In addition, the reference lists of identified relevant articles were also searched. Conclusions:The no-reflow phenomenon is characterised by damage to microvascular function and microstructure at ischaemia-reperfusion. Microemboli contribute to noreflow. Clinical myocardial contrast echocardiography (MCE), scintigraphic and magnetic resonance imaging (MRI) have shown evidence of microvascular damage, eg, perfusion defects are closely related to lack of contractile recovery and irreversible myocyte damage. Clinical agents and devices targeting microvascular injury (especially protection of endothelium and reduction of microemboli) after acute myocardial infarction may be key points to improve no-reflow.

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Section: (Iii) Fluids and Calcium Fluxmentioning

confidence: 99%

Coronary microvascular reperfusion injury and no-reflow in acute myocardial infarction

Kang

Yang

2007

CIM

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“…Endothelial cells were obtained as previously described in detail. 28 To analyze cGMP in the whole hearts, hearts were pulverized under liquid nitrogen and homogenized in cold trichloroacetic acid at 7.5% (wt/vol). After centrifugation (14,000g, 15 minutes, 4°C), the supernatant was collected and washed with water-saturated diethylether.…”

Section: Cgmp Contentmentioning

confidence: 99%

“…cGMP content in myocytes and endothelial cells was assessed in ethanol extracts from the corresponding cell cultures, dried, and resuspended in acetate buffer (5 mmol/L, pH 4.8). cGMP was measured in the extracts by radioimmunoassay using acetylated [ 3 H]-cGMP as previously described, 28 and results were expressed as femtomoles of cGMP per milligram of protein.…”

Section: Cgmp Contentmentioning

confidence: 99%

Left ventricular hypertrophy in rats with biliary cirrhosis

et al. 2003

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Portal hypertension induces neuroendocrine activation and a hyperkinetic circulation state. This study investigated the consequences of portal hypertension on heart structure and function. Intrahepatic portal hypertension was induced in male Sprague-Dawley rats by chronic bile duct ligation (CBDL). Six weeks later, CBDL rats showed higher plasma angiotensin-II and endothelin-1 (P < .01), 56% reduction in peripheral resistance and 73% reduction in pulmonary resistance (P < .01), 87% increase in cardiac index and 30% increase in heart weight (P < .01), and increased myocardial nitric oxide (NO) synthesis. In CBDL rats, macroscopic analysis demonstrated a 30% (P < .01) increase in cross-sectional area of the left ventricular (LV) wall without changes in the LV cavity or in the right ventricle (RV). Histomorphometric analysis revealed increased cell width (12%, P < .01) of cardiomyocytes from the LV of CBDL rats, but no differences in myocardial collagen content. Myocytes isolated from the LV were wider (12%) and longer (8%) than right ventricular myocytes (P < .01) in CBDL rats but not in controls. CBDL rats showed an increased expression of ANF and CK-B genes (P < .01). Isolated perfused CBDL hearts showed pressure/end-diastolic pressure curves and response to isoproterenol identical to sham hearts, although generated wall tension was reduced because of the increased wall thickness. Coronary resistance was markedly reduced. This reduction was abolished by inhibition of NO synthesis with N-nitro-L-arginine. Expression of eNOS was increased in CBDL hearts. In conclusion, portal hypertension associated to biliary cirrhosis induces marked LV hypertrophy and increased myocardial NO synthesis without detectable fibrosis or functional impairment. This observation could be relevant to patients with cirrhosis. (HEPATOLOGY 2003;38:589-598.) H yperdynamic circulation is a common feature in human and experimental portal hypertension, with or without cirrhosis. This is also called hyperdynamic circulatory syndrome and is the consequence of splanchnic and systemic vasodilatation, manifested by increased heart rate, cardiac output, and regional blood flow with decreased mean arterial pressure and systemic vascular resistance (SVR). 1 The mechanism of systemic and splanchnic vasodilatation is multifactorial. Many studies have suggested a prominent role for increased biosynthesis of nitric oxide (NO), 2 which is due to increased endothelial nitric oxide synthase (eNOS) activity. 3,4 It has been shown that NO inhibition attenuates the hyperdynamic circulation observed in portal hypertensive rats. 5,6 Other studies have shown an increased splanchnic production of carbon monoxide in portal hypertension 7 as well as an increased release of splanchnic vasodilatory peptides, such as glucagon. 8,9 Vasoconstrictor systems are also up-regulated, probably as a counter-regulatory response to the hyperdynamic state. 10 Sympathetic nervous and renin-angiotensin aldosterone systems are enhanced, and the plasma levels of vasopressin and endot...

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“…Because acidosis often coexists with hypoxia, the role of acidosis as an independent modulator of vascular cell behavior has, until recently, been overlooked. However, recent studies in vitro and in vivo support the idea that EA has cellular effects independent of hypoxia (2,9,21,27,32,35).Heme oxygenase (HO) and its enzymatic products biliverdin and CO have received increasing recognition as biologically important modulators of cellular interactions in the vasculature. The inducible form of this enzyme, HO-1, is ubiquitously distributed in mammalian tissues, and its expression is regulated by a number of nonheme inducers such as cytokines, heavy metals, hormones and endotoxin (1).…”

mentioning

confidence: 99%

mentioning

confidence: 99%

Extracellular acidosis induces heme oxygenase-1 expression in vascular smooth muscle cells

Christou

Bailey

Kluger

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

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acidosis (EA) has profound effects on vascular homeostasis, including vascular bed-specific alterations in vascular tone. Regulation of gene expression by EA has been observed in a variety of cells including vascular endothelial cells. Whether EA regulates gene expression in vascular smooth muscle cells (VSMCs) is not known. Heme oxygenase (HO)-1 is expressed in vascular cells, and its expression is regulated by cellular stressors such as heat, radiation, and hypoxia. Increased HO-1 expression in VSMCs leads to increased production of CO and its second messenger cGMP, which are important regulators of vascular tone and paracrine interactions in the vasculature. We examined whether EA regulates the expression of HO-1 in VSMCs. Exposure of VSMCs to acidic medium (pH 6.8) significantly increased HO-1 mRNA and protein compared with exposure to medium of physiological pH (pH 7.4). The acidic induction of HO-1 expression was time dependent and involved both transcriptional activation of the HO-1 gene and enhanced stability of HO-1 mRNA. Nitric oxide did not appear to mediate this response. We conclude that HO-1 is transcriptionally and posttranscriptionally upregulated by EA in VSMCs. This induction is time dependent and reversible. We speculate that EA, as an important tissue and cellular stressor for VSMCs, may elicit changes in gene expression patterns that contribute to the maintenance or disruption of vascular homeostasis. transcriptional activation; ribonucleic acid stabilization EXTRACELLULAR ACIDOSIS (EA) is a common clinical state that has profound cardiovascular effects. Although extracellular pH is normally maintained within narrow limits around 7.4, a number of acute and chronic disorders disrupt the acid-base homeostatic mechanisms and lead to systemic acidemia. In addition, local tissue acidosis is found in areas of inflammation, ischemia, and/or hypoxia as well as within solid tumors (36). Systemic acidemia leads to vascular bed-specific alterations in vascular tone and modulation of cardiac contractility. Local tissue acidosis is an important modulator of tumor invasiveness (20) and susceptibility of tumors to radiation, chemotherapy (20), and antiangiogenic therapy (34). The cellular and molecular events mediating the effects of acidosis on vascular homeostasis are incompletely understood. Because acidosis often coexists with hypoxia, the role of acidosis as an independent modulator of vascular cell behavior has, until recently, been overlooked. However, recent studies in vitro and in vivo support the idea that EA has cellular effects independent of hypoxia (2,9,21,27,32,35).Heme oxygenase (HO) and its enzymatic products biliverdin and CO have received increasing recognition as biologically important modulators of cellular interactions in the vasculature. The inducible form of this enzyme, HO-1, is ubiquitously distributed in mammalian tissues, and its expression is regulated by a number of nonheme inducers such as cytokines, heavy metals, hormones and endotoxin (1). In addition, a number of cellular ...

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Hypoxia and acidosis impair cGMP synthesis in microvascular coronary endothelial cells

Cited by 32 publications

References 41 publications

Coronary microvascular reperfusion injury and no-reflow in acute myocardial infarction

Coronary microvascular reperfusion injury and no-reflow in acute myocardial infarction

Left ventricular hypertrophy in rats with biliary cirrhosis

Extracellular acidosis induces heme oxygenase-1 expression in vascular smooth muscle cells

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