Gender-Related Differences in Atherosclerosis

Mathur, Pankaj; Ošťádal, B; Romeo, Francesco; Mehta, Jawahar L.

doi:10.1007/s10557-015-6596-3

Cited by 84 publications

(75 citation statements)

References 66 publications

(108 reference statements)

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“…The stronger associations for total apoC‐III with CAC in men and more divergent associations between the 2 HDL subspecies in women may largely reflect the considerable differences in exposure and outcome distributions by sex; all apolipoprotein levels were higher in women, whereas CAC scores were substantially higher in men. Sex differences in lipid metabolism or in the determinants or pathophysiological characteristics of atherosclerosis may also contribute to the discrepant findings for men and women in baseline CAC analyses.…”

Section: Discussionmentioning

confidence: 99%

High‐Density Lipoprotein Subspecies Defined by Apolipoprotein C‐III and Subclinical Atherosclerosis Measures: MESA (The Multi‐Ethnic Study of Atherosclerosis)

Aroner

Koch

Mukamal

et al. 2018

JAHA

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BackgroundApolipoprotein C‐III (apoC‐III), a small proinflammatory protein present on 6% to 7% of high‐density lipoprotein (HDL) particles, defines a subspecies of HDL adversely associated with coronary heart disease in primarily white cohorts. In a multi‐ethnic population free of clinical cardiovascular disease, we evaluated the relationship between apoC‐III–defined HDL subspecies and subclinical markers of atherosclerotic pathology.Methods and ResultsWe investigated cross‐sectional associations between apolipoprotein A‐I concentrations of apoC‐III–defined HDL subspecies, measured via ELISA and imaging measures of subclinical atherosclerosis, among 4659 participants in the MESA (The Multi‐Ethnic Study of Atherosclerosis) at baseline (2000–2002). HDL particles containing and lacking apoC‐III were divergently associated with coronary artery calcification in women (P‐heterogeneity=0.002) but not in men (P‐heterogeneity=0.31) and with carotid plaque score (P‐heterogeneity=0.02) and intima‐media thickness (P‐heterogeneity=0.06) in the overall study population. HDL lacking apoC‐III was inversely associated with all outcome measures (coronary artery calcification, women: odds ratio per SD=0.81 [95% confidence interval [CI], 0.73–0.90]; carotid plaque, overall: odds ratio per SD=0.92 [95% CI, 0.84–1.00]; intima‐media thickness, overall: mean difference per SD=−14.0 µm [95% CI, −21.1 to −6.7 μm]), whereas HDL containing apoC‐III was positively associated (coronary artery calcification, women: odds ratio=1.10 [95% CI, 0.99–1.22]; plaque, overall: odds ratio=1.10 [95% CI, 1.01–1.19]) or unassociated. Neither total HDL nor HDL subspecies was associated with changes in subclinical atherosclerosis measures up to 10 years later.ConclusionsThe presence of apoC‐III defined a subspecies of HDL not inversely associated with baseline measures of subclinical atherosclerosis, supporting a role of apoC‐III in the pathophysiology of cardiovascular disease.

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Section: Discussionmentioning

confidence: 99%

High‐Density Lipoprotein Subspecies Defined by Apolipoprotein C‐III and Subclinical Atherosclerosis Measures: MESA (The Multi‐Ethnic Study of Atherosclerosis)

Aroner

Koch

Mukamal

et al. 2018

JAHA

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“…The male sex is commonly recognized as an independent risk factor for cardiovascular disease [34]. In male Apoe -deficient mice, previous studies showed that a lack of the vascular integrin Itga8 is associated with aggravated atherosclerosis and the development of renal injury [5].…”

Section: Discussionmentioning

confidence: 99%

Sex differences in the development of vascular and renal lesions in mice with a simultaneous deficiency of Apoe and the integrin chain Itga8

et al. 2017

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Background Apoe-deficient (Apoe −/−) mice develop progressive atherosclerotic lesions with age but no severe renal pathology in the absence of additional challenges. We recently described accelerated atherosclerosis as well as marked renal injury in Apoe −/− mice deficient in the mesenchymal integrin chain Itga8 (Itga8 −/−). Here, we used this Apoe −/−, Itga8 −/− mouse model to investigate the sex differences in the development of atherosclerosis and concomitant renal injury. We hypothesized that aging female mice are protected from vascular and renal damage in this mouse model.Methods Apoe −/− mice were backcrossed with Itga8 −/− mice. Mice were kept on a normal diet. At the age of 12 months, the aortae and kidneys of male and female Apoe −/− Itga8 +/+ mice or Apoe −/− Itga8 −/− mice were studied. En face preparations of the aorta were stained with Sudan IV (lipid deposition) or von Kossa (calcification). In kidney tissue, immunostaining for collagen IV, CD3, F4/80, and PCNA and real-time PCR analyses for Il6, Vegfa, Col1a1 (collagen I), and Ssp1 (secreted phosphoprotein 1, synonym osteopontin) as well as ER stress markers were performed.ResultsWhen compared to male mice, Apoe −/− Itga8 +/+ female mice had a lower body weight, equal serum cholesterol levels, and lower triglyceride levels. However, female mice had increased aortic lipid deposition and more aortic calcifications than males. Male Apoe −/− mice with the additional deficiency of Itga8 developed increased serum urea, glomerulosclerosis, renal immune cell infiltration, and reduced glomerular cell proliferation. In females of the same genotype, these renal changes were less pronounced and were accompanied by lower expression of interleukin-6 and collagen I, while osteopontin expression was higher and markers of ER stress were not different.ConclusionsIn this model of atherosclerosis, the female sex is a risk factor to develop more severe atherosclerotic lesions, even though serum fat levels are higher in males. In contrast, female mice are protected from renal damage, which is accompanied by attenuated inflammation and matrix deposition. Thus, sex affects vascular and renal injury in a differential manner.Electronic supplementary materialThe online version of this article (doi:10.1186/s13293-017-0141-y) contains supplementary material, which is available to authorized users.

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“…The gender dependent significant differences in the cell death pathways following ischemic insults and in pharmacotherapy and some diseases have reported (Mathur et al, 2015; Rosano et al, 2015). The limitations of this study is that only male rats were used in present study, so biological sex difference of rifampicin was not investigated.…”

Section: Discussionmentioning

confidence: 99%

Rifampicin Attenuated Global Cerebral Ischemia Injury via Activating the Nuclear Factor Erythroid 2-Related Factor Pathway

Chen¹,

Cao²,

Chen

et al. 2016

Front. Cell. Neurosci.

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Background: Recent studies have found that rifampicin has neuroprotective properties in neurodegenerative diseases. However, the exact mechanisms of action remain unclear. The nuclear factor erythroid 2-related factor 2 (Nrf2) has been considered a potential target for neuroprotection. In this study, we examined whether rifampicin exhibits beneficial effects mediated by the Nrf2 pathway after global cerebral ischemia (GCI).Methods: Rats were randomly assigned to four groups that included a sham group and three treatment groups with global ischemia-reperfusion [control, rifampicin, and rifampicin plus brusatol (an inhibitor of Nrf2)]. Rats were subjected to transient GCI induced by bilateral common carotid artery occlusion for 20 min with systemic hypotension by blood withdrawal. The Morris water maze test was performed for neurobehavioral testing, whereas the pathological changes were investigated using HE and TUNEL staining. The protein expression of Nrf2, hemeoxygenase-1 (HO-1) and cyclooxygenase-2 (COX-2) in the hippocampus were analyzed by Western blotting. The immunofluorescence staining was used to determine the distribution of Nrf2.Results: Rifampicin treatment significantly improved spatial learning ability compared with the control group, which was consistent with the pathological changes. In addition, rifampicin significantly elevated the nuclear expression of Nrf2, Nrf2 downstream anti-oxidant protein, HO-1 compared with the control group, and it simultaneously downregulated the expression of COX-2 in the hippocampus on day 3 after ischemia-reperfusion. Interestingly, the forenamed effects of rifampicin were abolished by pretreatment with brusatol, a specific inhibitor of Nrf2 activation.Conclusions: Rifampicin exerts neuroprotective effects against global cerebral ischemia, which may be attributed to activation of the Nrf2 pathway.

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Gender-Related Differences in Atherosclerosis

Cited by 84 publications

References 66 publications

High‐Density Lipoprotein Subspecies Defined by Apolipoprotein C‐III and Subclinical Atherosclerosis Measures: MESA (The Multi‐Ethnic Study of Atherosclerosis)

High‐Density Lipoprotein Subspecies Defined by Apolipoprotein C‐III and Subclinical Atherosclerosis Measures: MESA (The Multi‐Ethnic Study of Atherosclerosis)

Sex differences in the development of vascular and renal lesions in mice with a simultaneous deficiency of Apoe and the integrin chain Itga8

Rifampicin Attenuated Global Cerebral Ischemia Injury via Activating the Nuclear Factor Erythroid 2-Related Factor Pathway

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