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Papers by M. Iruela-arispe

Research paper thumbnail of Time and dose effect of transdermal nicotine on endothelial function

American Journal of Physiology-Heart and Circulatory Physiology, 2000

Nicotine patches are available as an over-the-counter medication for aid in smoking cessation. Th... more Nicotine patches are available as an over-the-counter medication for aid in smoking cessation. This study was designed to determine how nicotine patch therapy over time and dose ranges used in smoking cessation programs in humans affects endothelium-dependent relaxations. Dogs were treated with nicotine patches (11, 22, or 44 mg/day) for 2 and 5 wk. Circulating nicotine and oxidized products of nitric oxide (NOx) were measured. Coronary arteries were prepared for measurement of isometric force and aortic endothelial cells were prepared for measurement of mRNA or NO synthase (NOS) activity. Circulating nicotine increased with increasing concentrations of nicotine patches. After 5 wk of treatment with 22 mg/day patches, circulating NOx was reduced but NOS activity was increased. NOS mRNA was similar among groups. Only after 5 wk of treatment with 22 mg/day patches were endothelium-dependent relaxations reduced to α2-adrenergic agonists, ADP, and the calcium ionophore A-23187. These re...

Research paper thumbnail of The KEEPS-Cognitive and Affective Study: baseline associations between vascular risk factors and cognition

Journal of Alzheimer's disease : JAD, 2014

Midlife vascular risk factors influence later cognitive decline and Alzheimer's disease (AD).... more Midlife vascular risk factors influence later cognitive decline and Alzheimer's disease (AD). The decrease in serum estradiol levels during menopause has been associated with cognitive impairment and increased vascular risk, such as high blood pressure (BP), which independently contributes to cognitive dysfunction and AD. We describe the extent to which vascular risk factors relate to cognition in healthy, middle-aged, recently postmenopausal women enrolled in the Kronos Early Estrogen Prevention Cognitive and Affective Study (KEEPS-Cog) at baseline. KEEPS-Cog is a double-blind, randomized, placebo-controlled, parallel group, clinical trial, investigating the efficacy of low-dose, transdermal 17β-estradiol and oral conjugated equine estrogen on cognition. All results are cross-sectional and represent baseline data only. Analyses confirm that the KEEPS-Cog cohort (n = 571) was middle aged (mean 52.7 years, range 42-59 years), healthy, and free of cognitive dysfunction. Higher sys...

Research paper thumbnail of NIH initiative to balance sex of animals in preclinical studies: generative questions to guide policy, implementation, and metrics

Biology of Sex Differences, 2014

In May of 2014, the NIH Director together with the Director of the Office of Research on Women's ... more In May of 2014, the NIH Director together with the Director of the Office of Research on Women's Health announced plans to take a multi-dimensional approach to address the over reliance on male cells and animals in preclinical research. The NIH is engaging the scientific community in the development of policies to improve the sex balance in research. The present, past, and future presidents of the Organization for the Study of Sex Differences, in order to encourage thoughtful discussion among scientists, pose a series of questions to generate ideas in three areas: 1. research strategies, 2. educational strategies, and 3. strategies to monitor effectiveness of policies to improve the sex balance in research. By promoting discussion within the scientific community, a consensus will evolve that will move science forward in a productive and effective manner.

Research paper thumbnail of Loss of estrogen receptor β decreases mitochondrial energetic potential and increases thrombogenicity of platelets in aged female mice

AGE, 2009

Platelets derived from aged (reproductively senescent) female mice with genetic deletion of estro... more Platelets derived from aged (reproductively senescent) female mice with genetic deletion of estrogen receptor beta (βER) are more thrombogenic than those from age-matched wild-type (WT) mice. Intracellular processes contributing to this increased thrombogenicity are not known. Experiments were designed to identify subcellular localization of estrogen receptors and evaluate both glycolytic and mitochondrial energetic processes which might affect platelet activation. Platelets and blood from aged (22-24 months) WT and estrogen receptor β knockout (βERKO) female mice were used in this study. Body, spleen weight, and serum concentrations of follicle-stimulating hormone and 17β-estradiol were comparable between WT and βERKO mice. Number of spontaneous deaths was greater in the βERKO colony (50% compared to 30% in WT) over the course of 24 months. In resting (nonactivated) platelets, estrogen receptors did not appear to colocalize with mitochondria by immunostaining. Lactate production and mitochondrial membrane potential of intact platelets were similar in both groups of mice. However, activities of NADH dehydrogenase, cytochrome bc 1 complex, and cytochrome c oxidase of the electron transport chain were reduced in mitochondria isolated from platelets from βERKO compared to WT mice. There were a significantly higher number of phosphatidylserine-expressing platelet-derived microvesicles in the plasma and a greater thrombin-generating capacity in βERKO compared to WT mice. These results suggest that deficiencies in βER affect energy metabolism of platelets resulting in greater production of circulating thrombogenic microvesicles and could potentially explain increased predisposition to thromboembolism in some elderly females.

Research paper thumbnail of Intra-thoracic fat, cardiometabolic risk factors, and subclinical cardiovascular disease in healthy, recently menopausal women screened for the Kronos Early Estrogen Prevention Study (KEEPS)

Atherosclerosis, 2012

Objective-To examine the correlations between intra-hepatic and intra-thoracic (total, epicardial... more Objective-To examine the correlations between intra-hepatic and intra-thoracic (total, epicardial, and pericardial) fat deposition with cardiovascular disease (CVD) risk factors and subclinical atherosclerosis burden in healthy, recently postmenopausal women. Methods-Women screened for the Kronos Early Estrogen Prevention Study (mean age 52.9 years) who underwent electron beam or multidetector computed tomography (CT) imaging for the quantification of intra-hepatic fat and thoracic adipose tissue, and coronary artery calcification (CAC) were included (n= 650). Results-Higher levels of intra-hepatic and thoracic fat were each associated with CVD risk markers. After adjustment for BMI, the associations for intra-hepatic fat with hs-CRP and insulin persisted (r= 0.21 and 0.19, respectively; P<0.001), while those between thoracic fat indices and lipids persisted (r for total thoracic fat with HDL, LDL, and triglycerides= −0.16, 0.11, and 0.11, respectively, P<0.05). Total thoracic fat was associated with CAC after initial multivariable adjustment (odds ratio [OR] of 2 nd , 3 rd , and 4 th vs. 1 st quartile and [95% confidence intervals]: 0.8 [0.4-1.6], 1.5 [0.8-2.9], and 1.8 [1.0-3.4]; P for linear trend=0.017) and was only slightly attenuated after additional adjustment for BMI. Associations between total thoracic fat and CVD risk markers and CAC appeared due slightly more to associations with epicardial than pericardial fat. Conclusion-While hepatic fat is related to hs-CRP and insulin, cardiac fat is associated with subclinical atherosclerosis as demonstrated by CAC. Cardiac fat may represent a useful marker for increased CVD risk beyond the standard adiposity measures of BMI and WC.

Research paper thumbnail of NIH initiative to balance sex of animals in preclinical studies: generative questions to guide policy, implementation, and metrics

Biology of Sex Differences, 2014

In May of 2014, the NIH Director together with the Director of the Office of Research on Women's ... more In May of 2014, the NIH Director together with the Director of the Office of Research on Women's Health announced plans to take a multi-dimensional approach to address the over reliance on male cells and animals in preclinical research. The NIH is engaging the scientific community in the development of policies to improve the sex balance in research. The present, past, and future presidents of the Organization for the Study of Sex Differences, in order to encourage thoughtful discussion among scientists, pose a series of questions to generate ideas in three areas: 1. research strategies, 2. educational strategies, and 3. strategies to monitor effectiveness of policies to improve the sex balance in research. By promoting discussion within the scientific community, a consensus will evolve that will move science forward in a productive and effective manner.

Research paper thumbnail of Time and dose effect of transdermal nicotine on endothelial function

American Journal of Physiology-Heart and Circulatory Physiology, 2000

Nicotine patches are available as an over-the-counter medication for aid in smoking cessation. Th... more Nicotine patches are available as an over-the-counter medication for aid in smoking cessation. This study was designed to determine how nicotine patch therapy over time and dose ranges used in smoking cessation programs in humans affects endothelium-dependent relaxations. Dogs were treated with nicotine patches (11, 22, or 44 mg/day) for 2 and 5 wk. Circulating nicotine and oxidized products of nitric oxide (NOx) were measured. Coronary arteries were prepared for measurement of isometric force and aortic endothelial cells were prepared for measurement of mRNA or NO synthase (NOS) activity. Circulating nicotine increased with increasing concentrations of nicotine patches. After 5 wk of treatment with 22 mg/day patches, circulating NOx was reduced but NOS activity was increased. NOS mRNA was similar among groups. Only after 5 wk of treatment with 22 mg/day patches were endothelium-dependent relaxations reduced to α2-adrenergic agonists, ADP, and the calcium ionophore A-23187. These re...

Research paper thumbnail of The KEEPS-Cognitive and Affective Study: baseline associations between vascular risk factors and cognition

Journal of Alzheimer's disease : JAD, 2014

Midlife vascular risk factors influence later cognitive decline and Alzheimer's disease (AD).... more Midlife vascular risk factors influence later cognitive decline and Alzheimer's disease (AD). The decrease in serum estradiol levels during menopause has been associated with cognitive impairment and increased vascular risk, such as high blood pressure (BP), which independently contributes to cognitive dysfunction and AD. We describe the extent to which vascular risk factors relate to cognition in healthy, middle-aged, recently postmenopausal women enrolled in the Kronos Early Estrogen Prevention Cognitive and Affective Study (KEEPS-Cog) at baseline. KEEPS-Cog is a double-blind, randomized, placebo-controlled, parallel group, clinical trial, investigating the efficacy of low-dose, transdermal 17β-estradiol and oral conjugated equine estrogen on cognition. All results are cross-sectional and represent baseline data only. Analyses confirm that the KEEPS-Cog cohort (n = 571) was middle aged (mean 52.7 years, range 42-59 years), healthy, and free of cognitive dysfunction. Higher sys...

Research paper thumbnail of NIH initiative to balance sex of animals in preclinical studies: generative questions to guide policy, implementation, and metrics

Biology of Sex Differences, 2014

In May of 2014, the NIH Director together with the Director of the Office of Research on Women's ... more In May of 2014, the NIH Director together with the Director of the Office of Research on Women's Health announced plans to take a multi-dimensional approach to address the over reliance on male cells and animals in preclinical research. The NIH is engaging the scientific community in the development of policies to improve the sex balance in research. The present, past, and future presidents of the Organization for the Study of Sex Differences, in order to encourage thoughtful discussion among scientists, pose a series of questions to generate ideas in three areas: 1. research strategies, 2. educational strategies, and 3. strategies to monitor effectiveness of policies to improve the sex balance in research. By promoting discussion within the scientific community, a consensus will evolve that will move science forward in a productive and effective manner.

Research paper thumbnail of Loss of estrogen receptor β decreases mitochondrial energetic potential and increases thrombogenicity of platelets in aged female mice

AGE, 2009

Platelets derived from aged (reproductively senescent) female mice with genetic deletion of estro... more Platelets derived from aged (reproductively senescent) female mice with genetic deletion of estrogen receptor beta (βER) are more thrombogenic than those from age-matched wild-type (WT) mice. Intracellular processes contributing to this increased thrombogenicity are not known. Experiments were designed to identify subcellular localization of estrogen receptors and evaluate both glycolytic and mitochondrial energetic processes which might affect platelet activation. Platelets and blood from aged (22-24 months) WT and estrogen receptor β knockout (βERKO) female mice were used in this study. Body, spleen weight, and serum concentrations of follicle-stimulating hormone and 17β-estradiol were comparable between WT and βERKO mice. Number of spontaneous deaths was greater in the βERKO colony (50% compared to 30% in WT) over the course of 24 months. In resting (nonactivated) platelets, estrogen receptors did not appear to colocalize with mitochondria by immunostaining. Lactate production and mitochondrial membrane potential of intact platelets were similar in both groups of mice. However, activities of NADH dehydrogenase, cytochrome bc 1 complex, and cytochrome c oxidase of the electron transport chain were reduced in mitochondria isolated from platelets from βERKO compared to WT mice. There were a significantly higher number of phosphatidylserine-expressing platelet-derived microvesicles in the plasma and a greater thrombin-generating capacity in βERKO compared to WT mice. These results suggest that deficiencies in βER affect energy metabolism of platelets resulting in greater production of circulating thrombogenic microvesicles and could potentially explain increased predisposition to thromboembolism in some elderly females.

Research paper thumbnail of Intra-thoracic fat, cardiometabolic risk factors, and subclinical cardiovascular disease in healthy, recently menopausal women screened for the Kronos Early Estrogen Prevention Study (KEEPS)

Atherosclerosis, 2012

Objective-To examine the correlations between intra-hepatic and intra-thoracic (total, epicardial... more Objective-To examine the correlations between intra-hepatic and intra-thoracic (total, epicardial, and pericardial) fat deposition with cardiovascular disease (CVD) risk factors and subclinical atherosclerosis burden in healthy, recently postmenopausal women. Methods-Women screened for the Kronos Early Estrogen Prevention Study (mean age 52.9 years) who underwent electron beam or multidetector computed tomography (CT) imaging for the quantification of intra-hepatic fat and thoracic adipose tissue, and coronary artery calcification (CAC) were included (n= 650). Results-Higher levels of intra-hepatic and thoracic fat were each associated with CVD risk markers. After adjustment for BMI, the associations for intra-hepatic fat with hs-CRP and insulin persisted (r= 0.21 and 0.19, respectively; P<0.001), while those between thoracic fat indices and lipids persisted (r for total thoracic fat with HDL, LDL, and triglycerides= −0.16, 0.11, and 0.11, respectively, P<0.05). Total thoracic fat was associated with CAC after initial multivariable adjustment (odds ratio [OR] of 2 nd , 3 rd , and 4 th vs. 1 st quartile and [95% confidence intervals]: 0.8 [0.4-1.6], 1.5 [0.8-2.9], and 1.8 [1.0-3.4]; P for linear trend=0.017) and was only slightly attenuated after additional adjustment for BMI. Associations between total thoracic fat and CVD risk markers and CAC appeared due slightly more to associations with epicardial than pericardial fat. Conclusion-While hepatic fat is related to hs-CRP and insulin, cardiac fat is associated with subclinical atherosclerosis as demonstrated by CAC. Cardiac fat may represent a useful marker for increased CVD risk beyond the standard adiposity measures of BMI and WC.

Research paper thumbnail of NIH initiative to balance sex of animals in preclinical studies: generative questions to guide policy, implementation, and metrics

Biology of Sex Differences, 2014

In May of 2014, the NIH Director together with the Director of the Office of Research on Women's ... more In May of 2014, the NIH Director together with the Director of the Office of Research on Women's Health announced plans to take a multi-dimensional approach to address the over reliance on male cells and animals in preclinical research. The NIH is engaging the scientific community in the development of policies to improve the sex balance in research. The present, past, and future presidents of the Organization for the Study of Sex Differences, in order to encourage thoughtful discussion among scientists, pose a series of questions to generate ideas in three areas: 1. research strategies, 2. educational strategies, and 3. strategies to monitor effectiveness of policies to improve the sex balance in research. By promoting discussion within the scientific community, a consensus will evolve that will move science forward in a productive and effective manner.