American journal of physiology. Heart and circulatory physiology最新文献

Endothelial dysfunction is an early consequence of vascular inflammation and a driver of coronary atherosclerotic disease leading to myocardial infarction. The red blood cells (RBCs) mediate endothelial dysfunction in patients at cardiovascular risk, but their role in patients with acute myocardial infarction is unknown. This study aimed to investigate if RBCs from patients with ST-elevation myocardial infarction (STEMI) induced endothelial dysfunction and the role of systemic inflammation in this effect. RBCs from patients with STEMI and aged-matched healthy controls were co-incubated with rat aortic segments for 18h followed by evaluation of endothelium-dependent (EDR) and -independent relaxation (EIDR). RBCs and aortic segments were also analyzed for arginase and oxidative stress. The patients were divided into groups depending on C-reactive protein (CRP) levels at admission. RBCs from patients with STEMI and CRP levels >2 mg/L induced impairment of EDR, but not EIDR, compared to RBCs from STEMI and CRP <2 mg/L and healthy controls. Aortic expression of arginase 1 was increased following incubation with RBCs from patients with STEMI and CRP >2, and arginase inhibition prevented the RBC-induced endothelial dysfunction. RBCs from patients with STEMI and CRP >2 had increased reactive oxygen species compared to RBCs from patients with CRP <2 and healthy controls. Vascular inhibition of NADPH oxidases and increased dismutation of superoxide improved EDR. RBCs from patients with STEMI and low-grade inflammation induce endothelial dysfunction through a mechanism involving arginase 1 as well and increased RBC and vascular superoxide by NADPH oxidases.

Numerous genes including sarcospan (SSPN) have been designated as obesity-susceptibility genes by human genome-wide association studies. Variants in the SSPN locus have been linked with sex-dependent obesity-associated traits; however, this association has not been investigated in vivo. To delineate the role SSPN plays in regulating metabolism with potential to impact cardiac function, we subjected young and aged global SSPN-deficient (SSPN^-/-) male and female mice to obesogenic conditions (60% fat diet). We hypothesized that loss of SSPN combined with metabolic stress would increase susceptibility of mice to cardiometabolic disease. Baseline and end-point assessments of several anthropometric parameters were performed including weight, glucose tolerance, and fat distribution of mice fed control (CD) and high-fat (HFD) diet. Doppler echocardiography was used to monitor cardiac function. White adipose and cardiac tissues were assessed for inflammation by histological, gene expression, and cytokine analysis. Overall, SSPN deficiency protected both sexes and ages from diet-induced obesity, with a greater effect in females. SSPN^-/- HFD mice gained less weight than wild-type (WT) cohorts, while SSPN^-/- CD groups increased weight. Furthermore, aged SSPN^-/- mice developed glucose intolerance regardless of diet. Echocardiography showed preserved systolic function for all groups; however, aged SSPN^-/- males exhibited significant increases in left ventricular mass (CD) and signs of diastolic dysfunction (HFD). Cytokine analysis revealed significantly increased IL-1α and IL-17Α in white adipose tissue from young SSPN^-/- male mice, which may be protective from diet-induced obesity. Overall, these studies suggest that several sex-dependent mechanisms influence the role SSPN plays in metabolic responses that become evident with age.NEW & NOTEWORTHY Young and aged sarcospan (SSPN)-deficient mice were examined to assess the role of SSPN in obesity and cardiometabolic disease. Both sexes displayed a "leaner" phenotype in response to high-fat diet (HFD). Notably, several sex differences were identified in aged SSPN-deficient mice: 1) females developed glucose intolerance (control and HFD) and 2) males exhibited increased left ventricular mass (control) and diastolic dysfunction (HFD). Therefore, we conclude that SSPN exerts a sex-dependent influence on obesity-associated diseases.

Historical exclusion of females in research has been, in part, due to the perceived influence of natural menstrual (NAT) and oral contraceptive pill (OCP) cycles on vascular outcomes. NAT and OCP cycle phases may influence brachial artery (BA) endothelial function, however, findings are mixed. Minimal research has examined arterial stiffness, smooth muscle, and lower limb endothelial function. The purpose of this study was to investigate the influence of NAT and OCP cycles on cardiovascular outcomes and cellular regulation. Forty-nine premenopausal females (n = 17 NAT, n = 17 second generation OCP, n = 15 third generation OCP) participated in two randomized order visits in the low (LH, early follicular/placebo) and high (HH, midluteal/active) hormone cycle phases. BA and superficial femoral artery (SFA) endothelial function [flow-mediated dilation (FMD) test], smooth muscle function (nitroglycerine-mediated dilation test), and carotid and peripheral (pulse wave velocity) arterial stiffness were assessed. Cultured female human endothelial cells were exposed to participant serum for 24 h to examine endothelial nitric oxide synthase (eNOS) and estrogen receptor-α (ERα) protein content. BA FMD was elevated in the HH vs. LH phase, regardless of group (HH, 7.7 ± 3.5%; LH, 7.0 ± 3.3%; P = 0.02); however, allometric scaling for baseline diameter resulted in no phase effect (HH, 7.6 ± 2.6%; LH, 7.1 ± 2.6%; P = 0.052, d = 0.35). SFA FMD, BA, and SFA smooth muscle function, arterial stiffness, and eNOS and ERα protein content were unaffected. NAT and OCP phases examined have minimal influence on vascular outcomes and ERα-eNOS pathway, apart from a small effect on BA endothelial function partially explained by differences in baseline artery diameter. NEW & NOTEWORTHY Comprehensive evaluation of the cardiovascular system in naturally cycling and second and third generation OCP users indicates no major influence of hormonal phases examined on endothelial function and smooth muscle function in the arteries of the upper and lower limbs, arterial stiffness, or underlying cellular mechanisms. Study findings challenge the historical exclusion of female participants due to potentially confounding hormonal cycles; researchers are encouraged to consider the hormonal environment in future study design.

Blood pressure (BP) displays a circadian rhythm and disruptions in this pattern elevate cardiovascular risk. Although both central and peripheral clock genes are implicated in these processes, the importance of vascular clock genes is not fully understood. BP, vascular reactivity, and the renin-angiotensin-aldosterone system display overt sex differences, but whether changes in circadian patterns underlie these differences is unknown. Therefore, we hypothesized that circadian rhythms and vascular clock genes would differ across sex and would be blunted by angiotensin II (ANG II)-induced hypertension. ANG II infusion elevated BP and disrupted circadian patterns similarly in both males and females. In females, an impact on heart rate (HR) and locomotor activity was revealed, whereas in males hypertension suppressed baroreflex sensitivity (BRS). A marked disruption in the vascular expression patterns of period circadian regulator 1 (Per1) and brain and muscle aryl hydrocarbon receptor nuclear translocator like protein 1 (Bmal1) was noted in both sexes. Vascular expression of the G protein-coupled estrogen receptor (Gper1) also showed diurnal synchronization in both sexes that was similar to that of Per1 and Per2 and disrupted by hypertension. In contrast, vascular expression of estrogen receptor 1 (Esr1) showed a diurnal rhythm and hypertension-induced disruption only in females. This study shows a strikingly similar impact of hypertension on BP rhythmicity, vascular clock genes, and vascular estrogen receptor expression in both sexes. We identified a greater impact of hypertension on locomotor activity and heart rate in females and on baroreflex sensitivity in males and also revealed a diurnal regulation of vascular estrogen receptors. These insights highlight the intricate ties between circadian biology, sex differences, and cardiovascular regulation.NEW & NOTEWORTHY This study reveals that ANG II-induced hypertension disrupts the circadian rhythm of blood pressure in both male and female mice, with parallel effects on vascular clock gene and estrogen receptor diurnal patterns. Notably, sex-specific responses to hypertension in terms of locomotor activity, heart rate, and baroreflex sensitivity are revealed. These findings pave the way for chronotherapeutic strategies tailored to mitigate cardiovascular risks associated with disrupted circadian rhythms in hypertension.

Cerebrovascular and neurological diseases exhibit sex-specific patterns in prevalence, severity, and regional specificity, some of which are associated with altered cerebral blood flow (CBF). Females often exhibit higher resting CBF, but understanding the impact of sex per se on CBF is hampered by study variability in age, comorbidities, medications, and control for menstrual cycle or hormone therapies. A majority of studies report whole brain CBF without differentiating between gray and white matter or without assessing regional CBF. Thus fundamental sex differences in regional or whole brain CBF remain unclarified. While controlling for the above confounders, we tested the hypothesis that females will exhibit higher total gray and white matter perfusion as well as regional gray matter perfusion. Adults 18-30 yr old (females = 22 and males = 26) were studied using arterial spin labeling (ASL) magnetic resonance imaging (MRI) scans followed by computational anatomy toolbox (CAT12) analysis in statistical parametric mapping (SPM12) to quantify CBF relative to brain volume. Females displayed 40% higher perfusion globally (females = 62 ± 9 and males = 45 ± 10 mL/100 g/min, P < 0.001), gray matter (females = 75 ± 11 and males = 54 ± 12 mL/100 g/min, P < 0.001), and white matter (females = 44 ± 6 and males = 32 ± 7 mL/100 g/min, P < 0.001). Females exhibited greater perfusion than males in 67 of the 68 regions tested, ranging from 14% to 66% higher. A second MRI approach (4-dimensional flow) focused on large arteries confirmed the sex difference in global CBF. These data indicate strikingly higher basal CBF in females at global, gray, and white matter levels and across dozens of brain regions and offer new clarity into fundamental sex differences in global and regional CBF regulation before aging or pathology.NEW & NOTEWORTHY MRI used to measure cerebral blood flow (CBF) in gray matter, white matter, and 68 regions in healthy men and women. This study demonstrated that CBF is 40% higher in women, the highest sex difference reported, when controlling for numerous important clinical confounders like age, smoking, menstrual cycle, comorbidities, and medications.

Septic cardiomyopathy (SCM) with diastolic dysfunction carries a poor prognosis, and the mechanisms underlying the development of diastolic dysfunction remain unclear. Matrix metalloproteinase-8 (MMP-8) is released from neutrophils and degrades collagen I. MMP-8 levels correlate with SCM severity. We scrutinized, for the first time, the direct impact of MMP-8 on cardiac systolic and diastolic functions. Isolated rat hearts were perfused with Krebs-Henseleit solution in a Langendorff setup with computer-controlled filling pressures of both ventricles in an isovolumetric regime. The end-diastolic pressure (EDP) varied periodically between 3 and 20 mmHg. After baseline recordings, MMP-8 (100 µg/mL) was added to the perfusion. Short-axis views of both ventricles were continuously acquired by echocardiography. MMP-8 perfusion resulted in a progressive decline in peak systolic pressures (Psys) in both ventricles, but without significant changes in their end-systolic pressure-area relationships (ESPARs). Counterintuitively, conspicuous leftward shifts of the end-diastolic pressure-area relationships (EDPARs) were observed in both ventricles. The left ventricle (LV) end-diastolic area (EDA) decreased by 32.8 ± 5.7% (P = 0.008) at an EDP of 10.5 ± 0.4 mmHg, when LV Psys dropped by 20%. The decline of Psys was primarily due to the decrease in EDA, and restoring the baseline EDA by increasing EDP recovered 81.33 ± 5.87% of the pressure drop. Collagen I generates tensile (eccentric) stress, and its degradation by MMP-8 causes end-diastolic pressure-volume relationship (EDPVR) leftward shift, resulting in diastolic and systolic dysfunctions. The diastolic dysfunction explains the clinically observed fluid unresponsiveness, whereas the decrease in end-diastolic volume (EDV) diminishes the systolic functions. MMP-8 can explain the development of SCM with diastolic dysfunction.NEW & NOTEWORTHY MMP-8, released from activated neutrophils and macrophages, is markedly elevated in sepsis, correlating with sepsis severity and mortality. MMP-8 targets collagen I of the cardiac ECM and induces diastolic dysfunction with fluid unresponsiveness, associated with decreased EDV, reduced sarcomere length, and diminished systolic function. Unlike other MMPs that predominantly cleave collagen-III and contribute to cardiac dilatation, thereby increasing sarcomere length, MMP-8 leads to a leftward shift in the EDPVR, resulting in diastolic and systolic dysfunctions.