2-Methoxyestradiol in Pulmonary Arterial Hypertension: A New Disease Modifier

Pulmonary arterial hypertension (PAH), a debilitating and incurable disease, predominantly develops in women. Estradiol metabolism leads to the production of numerous metabolites with different levels of estrogenic activity and very often opposing biological effects. Dysregulated estradiol metabolism was recently linked to the penetrance, progression, and prognosis of the disease. Ongoing clinical trials are examining the effects of estradiol synthesis/signaling inhibition in patients with PAH. In this chapter, the effects of sex, sex hormones, and estradiol metabolism on the healthy pulmonary circulation and vascular pathobiology are discussed in the light of estradiol metabolism as potential pharmacological target in PAH. The effects of estrogens and their metabolites on vascular pathobiology and disease progression, their involvement in PAH-associated diseases, and the pros and cons for interventions at different levels of estradiol metabolism are discussed. Finally, we propose that 2-methoxyestradiol (2ME), a major non-estrogenic metabolite of estradiol, mediates at least in part the beneficial effects of estradiol and that 2ME exhibits opposing effects to estradiol on several processes relevant to the underlying pathophysiology of PAH, including angiogenesis, metabolic reprograming, inflammation, and immunity. Based on cellular and in vivo effects, 2ME should be viewed as a disease modifier in women with PAH

Long-term caffeine consumption exacerbates renal failure in obese, diabetic, ZSF1 (fa-facp) rats

Long-term caffeine consumption exacerbates renal failure in obese, diabetic, ZSF1 (fa-facp) rats.BackgroundOur preliminary studies indicate that chronic caffeine consumption has adverse renal effects in nephropathy associated with high blood pressure and insulin resistance. The purpose of this study was to investigate the effects of early (beginning at 8 weeks of age) and long-term (30 weeks) caffeine treatment (0.1% solution) on renal function and structure in obese, diabetic ZSF1 rats.MethodsMetabolic and renal function measurements were performed at six-week intervals and in a subset of animals (N = 6 per group) heart rate (HR) and mean arterial blood pressure (MABP) were monitored by a radiotelemetric technique. At the end of the study acute, measurements of renal hemodynamics and excretory function were conducted in anesthetized animals.ResultsCaffeine produced a very mild increase (4 to 5%) of MABP and HR, but greatly augmented proteinuria (P < 0.001), reduced creatinine clearance (P < 0.05) and had a mixed effect on metabolic status in obese ZSF1 rats. Caffeine significantly reduced body weight, glycosuria, fasting glucose and insulin levels and improved glucose tolerance, had no effect on elevated plasma triglycerides levels and significantly increased plasma cholesterol level (P < 0.001). Acute measurements of renal function revealed increased renal vascular resistance (95.1 ± 11 vs. 50.7 ± 2.4 mm Hg/mL/min/g kidney, P < 0.01) and decreased inulin clearance (0.37 ± 0.11 vs. 0.97 ± 0.13 mL/min/g kidney, P < 0.002) in caffeine-treated versus control animals, respectively. Caffeine potentiated the development of more severe tubulointerstitial changes (P < 0.05) and increased focal glomerulosclerosis (14.7 ± 1.7 vs. 6.5 ± 0.9%, caffeine vs. control, P < 0.002).ConclusionThe present study provides the first evidence that caffeine (despite improving insulin sensitivity) exacerbates renal failure in obese, diabetic ZSF1 rats. Further mechanistic studies of adverse renal effects of caffeine in chronic renal failure associated with metabolic syndrome are warranted

Role of Gender in Regulation of Redox Homeostasis in Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is one of the diseases with a well-established gender dimorphism. The prevalence of PAH is increased in females with a ratio of 4:1, while poor survival prognosis is associated with the male gender. Nevertheless, the specific contribution of gender in disease development and progression is unclear due to the complex nature of the PAH. Oxidative and nitrosative stresses are important contributors in PAH pathogenesis; however, the role of gender in redox homeostasis has been understudied. This review is aimed to overview the possible sex-specific mechanisms responsible for the regulation of the balance between oxidants and antioxidants in relation to PAH pathobiology

Experimental intravascular hemolysis induces hemodynamic and pathological pulmonary hypertension: association with accelerated purine metabolism

Pulmonary hypertension (PH) is emerging as a serious complication associated with hemolytic disorders, and plexiform lesions (PXL) have been reported in patients with sickle cell disease (SCD). We hypothesized that repetitive hemolysis per se induces PH and angioproliferative vasculopathy and evaluated a new mechanism for hemolysis-associated PH (HA-PH) that involves the release of adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP) from erythrocytes. In healthy rats, repetitive admin- istration of hemolyzed autologous blood (HAB) for 10 days produced reversible pulmonary parenchymal injury and vascular remodeling and PH. Moreover, the combination of a single dose of Sugen-5416 (SU, 200mg/kg) and 10-day HAB treatment resulted in severe and progressive obliterative PH and formation of PXL (Day 26, right ventricular peak systolic pressure (mmHg): 26.1 1.1, 41.5 0.5 and 85.1 5.9 in untreated, HAB treated and SUþHAB treated rats, respectively). In rats, repeti- tive administration of HAB increased plasma ADA activity and reduced urinary adenosine levels. Similarly, SCD patients had higher plasma ADA and PNP activity and accelerated adenosine, inosine, and guanosine metabolism than healthy controls. Our study provides evidence that hemolysis per se leads to the development of angioproliferative PH. We also report the development of a rat model of HA-PH that closely mimics pulmonary vasculopathy seen in patients with HA-PH. Finally, this study suggests that in hemolytic diseases released ADA and PNP may increase the risk of PH, likely by abolishing the vasoprotective effects of adenosine, inosine and guanosine. Further characterization of this new rat model of hemolysis-induced angioproliferative PH and additional studies of the role of purines metabolism in HA-PH are warranted

Dual A 1 /A 2B Receptor Blockade Improves Cardiac and Renal Outcomes in a Rat Model of Heart Failure with Preserved Ejection Fraction

ABSTRACT Heart failure with preserved ejection fraction (HFpEF) is prevalent and often accompanied by metabolic syndrome. Current treatment options are limited. Here, we test the hypothesis that combined A 1 /A 2B adenosine receptor blockade is beneficial in obese ZSF 1 rats, an animal model of HFpEF with metabolic syndrome. The combined A 1 /A 2B receptor antagonist 3-[4-(2,6-dioxo-1,3-dipropyl-7H-purin-8-yl)-1-bicyclo[2.2.2]octanyl]propanoic acid (BG9928) was administered orally (10 mg/kg/day) to obese ZSF 1 rats (n 5 10) for 24 weeks (from 20 to 44 weeks of age). Untreated ZSF 1 rats (n 5 9) served as controls. After 24 weeks of administration, BG9928 significantly lowered plasma triglycerides (in mg/dl: control group, 4351 6 550; BG9928 group, 2900 6 551) without adversely affecting plasma cholesterol or activating renin release. BG9928 significantly decreased 24-hour urinary glucose excretion (in mg/kg/day: control group, 823 6 179; BG9928 group, 196 6 80) and improved oral glucose tolerance, polydipsia, and polyuria. BG9928 significantly augmented left ventricular diastolic function in association with a reduction in cardiac vasculitis and cardiac necrosis. BG9928 significantly reduced 24-hour urinary protein excretion (in mg/kg/ day: control group, 1702 6 263; BG9928 group, 1076 6 238), and this was associated with a reduction in focal segmental glomerulosclerosis, tubular atrophy, tubular dilation, and deposition of proteinaceous material in the tubules. These findings show that, in a model of HFpEF with metabolic syndrome, A 1/ A 2B receptor inhibition improves hyperlipidemia, exerts antidiabetic actions, reduces HFpEF, improves cardiac histopathology, and affords renal protection. We conclude that chronic administration of combined A 1/ A 2B receptor antagonists could be beneficial in patients with HFpEF, in particular those with comorbidities such as obesity, diabetes, and dyslipidemias

Estradiol Metabolism: Crossroads in Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a debilitating and progressive disease that predominantly develops in women. Over the past 15 years, cumulating evidence has pointed toward dysregulated metabolism of sex hormones in animal models and patients with PAH. 17&beta;-estradiol (E2) is metabolized at positions C2, C4, and C16, which leads to the formation of metabolites with different biological/estrogenic activity. Since the first report that 2-methoxyestradiol, a major non-estrogenic metabolite of E2, attenuates the development and progression of experimental pulmonary hypertension (PH), it has become increasingly clear that E2, E2 precursors, and E2 metabolites exhibit both protective and detrimental effects in PH. Furthermore, both experimental and clinical data suggest that E2 has divergent effects in the pulmonary vasculature versus right ventricle (estrogen paradox in PAH). The estrogen paradox is of significant clinical relevance for understanding the development, progression, and prognosis of PAH. This review updates experimental and clinical findings and provides insights into: (1) the potential impacts that pathways of estradiol metabolism (EMet) may have in PAH; (2) the beneficial and adverse effects of estrogens and their precursors/metabolites in experimental PH and human PAH; (3) the co-morbidities and pathological conditions that may alter EMet and influence the development/progression of PAH; (4) the relevance of the intracrinology of sex hormones to vascular remodeling in PAH; and (5) the advantages/disadvantages of different approaches to modulate EMet in PAH. Finally, we propose the three-tier-estrogen effects in PAH concept, which may offer reconciliation of the opposing effects of E2 in PAH and may provide a better understanding of the complex mechanisms by which EMet affects the pulmonary circulation&ndash;right ventricular interaction in PAH

Recurrent inhibition of mitochondrial complex III induces chronic pulmonary vasoconstriction and glycolytic switch in the rat lung

Background: Pulmonary arterial hypertension (PAH) is a fatal disease; however, the mechanisms directly involved in triggering and the progression of PAH are not clear. Based on previous studies that demonstrated a possible role of mitochondrial dysfunction in the pathogenesis of PAH, we investigated the effects of chronic inhibition of mitochondrial function in vivo in healthy rodents. Methods: Right ventricle systolic pressure (RVSP) was measured in female rats at baseline and up to 24 days after inhibition of mitochondrial respiratory Complex III, induced by Antimycin A (AA, 035 mg/kg, given three times starting at baseline and then days 3 and 6 as a bolus injection into the right atrial chamber). Results: Rodents exposed to AA demonstrated sustained increases in RVSP from days 6 through 24. AA-exposed rodents also possessed a progressive increase in RV end-diastolic pressure but not RV hypertrophy, which may be attributed to either early stages of PAH development or to reduced RV contractility due to inhibition of myocardial respiration. Protein nitration levels in plasma were positively correlated with PAH development in AA-treated rats. This finding was strongly supported by results obtained from PAH humans where plasma protein nitration levels were correlated with markers of PAH severity in female but not male PAH patients. Based on previously reported associations between increased nitric oxide production levels with female gender, we speculate that in females with PAH mitochondrial dysfunction may represent a more deleterious form, in part, due to an increased nitrosative stress development. Indeed, the histological analysis of AA treated rats revealed a strong perivascular edema, a marker of pulmonary endothelial damage. Finally, AA treatment was accompanied by a severe metabolic shift toward glycolysis, a hallmark of PAH pathology. Conclusions: Chronic mitochondrial dysfunction induces the combination of vascular damage and metabolic reprogramming that may be responsible for PAH development. This mechanism may be especially important in females, perhaps due to an increased NO production and nitrosative stress development.NIH [1R01HL133085, R01HL136603, 1R01HL132918, 14SDG20480354]Open Access Journal.This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]