Eplerenone reduces arterial thrombosis in diabetic rats

Zakrzeska, Agnieszka; Gromotowicz-Popławska, Anna; Szemraj, Janusz; Szoka, Piotr; Kisiel, Wioleta; Purta, Tomasz; Kasacka, Irena; Chabielska, Ewa

doi:10.1177/1470320313515037

Cited by 16 publications

(11 citation statements)

References 53 publications

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“…32,33 There is also an association between elevated plasma aldosterone and Na + levels with increased incidence of coagulation and thrombotic events, which are mediated by aldosterone-induced AT1R signaling and blocked by mineralocorticoid receptor antagonists. [50][51][52][53] Along these line, thrombosis and occluded pulmonary ar- Figure 4. Effect of chronic hypoxia on circulating aldosterone levels in wild-type (WT) versus Cyp2c44 knockout (Cyp2c44 −/− ) female mice is shown.…”

Section: Discussionmentioning

confidence: 99%

Cyp2c44 Gene Disruption Exacerbated Pulmonary Hypertension and Heart Failure in Female but Not Male Mice

et al. 2016

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Epoxyeicosatrienoicacids (EETs), synthesized from arachidonic acid by epoxygenases of the CYP2C and CYP2J gene subfamilies, contribute to hypoxic pulmonary vasoconstriction (HPV) in mice. Despite their roles in HPV, it is controversial whether EETs mediate or ameliorate pulmonary hypertension (PH). A recent study showed that deficiency of Cyp2j did not protect male and female mice from hypoxia-induced PH. Since CYP2C44 is a functionally important epoxygenase, we hypothesized that knockout of the Cyp2c44 gene would protect both sexes of mice from hypoxia-induced PH. We tested this hypothesis in wild-type (WT) and Cyp2c44 knockout (Cyp2c44 (-/-)) mice exposed to normoxia (room air) and hypoxia (10% O2) for 5 weeks. Exposure of WT and Cyp2c44 (-/-) mice to hypoxia resulted in pulmonary vascular remodeling, increased pulmonary artery resistance, and decreased cardiac function in both sexes. However, in female Cyp2c44 (-/-) mice, compared with WT mice, (1) pulmonary artery resistance and right ventricular hypertrophy were greater, (2) cardiac index was lower, (3) left ventricular and arterial stiffness were higher, and (4) plasma aldosterone levels were higher, but (5) there was no difference in levels of EET in lungs and heart. Paradoxically and unexpectedly, we found that Cyp2c44 disruption exacerbated hypoxia-induced PH in female but not male mice. We attribute exacerbated PH in female Cyp2c44 (-/-) mice to elevated aldosterone and as-yet-unknown systemic factors. Therefore, we suggest a role for the human CYP2C genes in protecting women from severe PH and that this could be one of the underlying causes for a better 5-year survival rate in women than in men.

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Section: Discussionmentioning

confidence: 99%

Cyp2c44 Gene Disruption Exacerbated Pulmonary Hypertension and Heart Failure in Female but Not Male Mice

et al. 2016

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“…A blood morphology test was carried out using the hematological analyzer ScilVet ABC Plus+ (HORIBA ABX, Montpellier, France). A volumetric impedance method of counting blood cells was applied [ 54 ] for determination of white blood cells (WBCs), red blood cells (RBCs), medium cell volume (MCV), medium content of hemoglobin (MCH), medium cell hemoglobin concentration (MCHC), hemoglobin (HGB), platelet count (PLT), as well as automatic calculation of hematocrit (HCT).…”

Section: Methodsmentioning

confidence: 99%

Cannabidiol Ameliorates Monocrotaline-Induced Pulmonary Hypertension in Rats

Sadowska

Baranowska-Kuczko

Gromotowicz-Popławska

et al. 2020

IJMS

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Cannabidiol (CBD) is known for its vasorelaxant (including in the human pulmonary artery), anti-proliferative and anti-inflammatory properties. The aim of our study was to examine the potential preventive effect of chronic CBD administration (10 mg/kg/day for three weeks) on monocrotaline (MCT)-induced pulmonary hypertension (PH) rats. PH was connected with elevation of right ventricular systolic pressure; right ventricle hypertrophy; lung edema; pulmonary artery remodeling; enhancement of the vasoconstrictor and decreasing vasodilatory responses; increases in plasma concentrations of tissue plasminogen activator, plasminogen activator inhibitor type 1 and leukocyte count; and a decrease in blood oxygen saturation. CBD improved all abovementioned changes induced by PH except right ventricle hypertrophy and lung edema. In addition, CBD increased lung levels of some endocannabinoids (anandamide, N-arachidonoyl glycine, linolenoyl ethanolamide, palmitoleoyl ethanolamide and eicosapentaenoyl ethanolamide but not 2-arachidonoylglycerol). CBD did not affect the cardiopulmonary system of control rats or other parameters of blood morphology in PH. Our data suggest that CBD ameliorates MCT-induced PH in rats by improving endothelial efficiency and function, normalization of hemostatic alterations and reduction of enhanced leukocyte count determined in PH. In conclusion, CBD may be a safe, promising therapeutic or adjuvant therapy agent for the treatment of human pulmonary artery hypertension.

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“…In a rat model of thrombosis by vena cava ligation, acute Aldo administration enhanced thrombus burden, an effect that was prevented by co-treatment with eplerenone ( 47 ). Eplerenone also reduced post-carotid injury thrombosis in streptozotocin-induced diabetic rats ( 48 ). Aldo treatment has been shown to decrease bleeding time ( 49 ), induce platelet activation and degranulation, and increase expression of the thrombogenic plasminogen activator inhibitor [PAI-1 ( 50 )], whereas MR inhibitors increase bleeding time ( 49 ), decrease platelet activation ( 50 , 51 ), and inhibit expression of PAI-1, fibrinogen, P-selectin, and IL-1β in a variety of rodent models ( 48 , 51 , 52 ).…”

Section: Mr and Aldo In Plaque Rupture And Thrombus Formationmentioning

confidence: 99%

“…Eplerenone also reduced post-carotid injury thrombosis in streptozotocin-induced diabetic rats ( 48 ). Aldo treatment has been shown to decrease bleeding time ( 49 ), induce platelet activation and degranulation, and increase expression of the thrombogenic plasminogen activator inhibitor [PAI-1 ( 50 )], whereas MR inhibitors increase bleeding time ( 49 ), decrease platelet activation ( 50 , 51 ), and inhibit expression of PAI-1, fibrinogen, P-selectin, and IL-1β in a variety of rodent models ( 48 , 51 , 52 ). Paradoxically, Ducros et al ( 53 ) treated cultured human bone marrow ECs with Aldo and found an increase in the synthesis of the anti-thrombogenic endothelial protein C receptor (EPCR) and an increase in the clotting time of isolated plasma exposed to these ECs.…”

Section: Mr and Aldo In Plaque Rupture And Thrombus Formationmentioning

confidence: 99%

Mineralocorticoid Receptors in the Pathophysiology of Vascular Inflammation and Atherosclerosis

Moss

Jaffe

2015

Front. Endocrinol.

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Atherosclerosis is a chronic inflammatory disease of the vasculature that causes significant morbidity and mortality from myocardial infarction, stroke, and peripheral vascular disease. Landmark clinical trials revealed that mineralocorticoid receptor (MR) antagonists improve outcomes in cardiovascular patients. Conversely, enhanced MR activation by the hormone aldosterone is associated with increased risk of MI, stroke, and cardiovascular death. This review summarizes recent advances in our understanding of the role of aldosterone and the MR in the pathogenesis of vascular inflammation and atherosclerosis as it proceeds from risk factor-induced endothelial dysfunction and inflammation to plaque formation, progression, and ultimately rupture with thrombosis, the cause of acute ischemia. The role of the MR in converting cardiac risk factors into endothelial dysfunction, in enhancing leukocyte adhesion and infiltration into the vasculature, in promoting systemic inflammation and vascular oxidative stress, and in plaque destabilization and thrombosis are discussed. A greater understanding of the mechanisms by which the MR promotes atherosclerosis has substantial potential to identify novel treatment targets to improve cardiovascular health and decrease mortality.

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Eplerenone reduces arterial thrombosis in diabetic rats

Cited by 16 publications

References 53 publications

Cyp2c44 Gene Disruption Exacerbated Pulmonary Hypertension and Heart Failure in Female but Not Male Mice

Cyp2c44 Gene Disruption Exacerbated Pulmonary Hypertension and Heart Failure in Female but Not Male Mice

Cannabidiol Ameliorates Monocrotaline-Induced Pulmonary Hypertension in Rats

Mineralocorticoid Receptors in the Pathophysiology of Vascular Inflammation and Atherosclerosis

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