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

T-cell accumulation within the aorta promotes endothelial dysfunction and the genesis of cardiovascular disease, including hypertension and atherosclerosis. Viral infection during pregnancy is also known to mediate marked acute endothelial dysfunction, but it is not clear whether T cells are recruited to the aorta and whether the dysfunction persists postpartum. Here, we demonstrate that influenza A virus (IAV) infection during pregnancy in a murine model resulted in endothelial dysfunction of the aorta, which persisted for up to 60 days postinfection and was associated with higher levels of IFN-γ mRNA expression within the tissue. In the absence of infection, low numbers of naïve CD4⁺ and CD8⁺ T cells, central memory T cells, and effector memory T cells were observed in the aorta. However, with IAV infection, these T-cell subsets were significantly increased with a notable accumulation of IAV-specific CD8⁺ effector memory T cells. Critically, this increase was maintained out to at least 60 days. In contrast, IAV infection in nonpregnant female mice resulted in modest endothelial dysfunction with no accumulation of T cells within the aorta. These data, therefore, demonstrate that the aorta is a site of T-cell recruitment and retention after IAV infection during pregnancy. Although IAV-specific memory T cells could theoretically confer protection against future influenza infection, nonspecific memory T-cell activation and IFN-γ production in the aorta could also contribute to future endothelial dysfunction and cardiovascular disease.NEW & NOTEWORTHY Pregnancy is a risk factor for cardiovascular complications to influenza A virus (IAV) infection. We demonstrate that gestational IAV infection caused endothelial dysfunction of the maternal aorta, which persisted for 60 days postinfection in mice. Various T cells accumulated within the aorta at 60 days because of the infection, and this was associated with elevated levels of the proinflammatory cytokine, IFN-γ. Our study demonstrates a novel "long influenza" cardiovascular phenotype in female mice.

Exaggerated blood pressure (BP) responses during exercise are independently associated with future development of hypertension. Partial sleep deprivation (PSD) can increase 24-h ambulatory BP, but the effects on exercise BP are unclear. We hypothesized that acute PSD would augment the BP response to constant load cycling exercise and a 20-min time trial. Twenty-two healthy adults (22 ± 3 yr old; 13 males; V̇o_2peak, 43.6 ± 8.2 mL·kg^-1·min^-1) completed a randomized crossover trial in which they either slept normally (normal sleep-wake schedule for each participant) or sleep was partially deprived (early awakening, 40% of normal sleep duration). Each participant completed a 12-min warm-up consisting of two 6-min steps (step 1, 62 ± 25 W; step 2, 137 ± 60 W) followed by a 20-min time trial on a cycle ergometer. PSD did not alter power output during the 20-min time trial [(control vs. PSD) 170 ± 68 vs. 168 ± 68 W, P = 0.65]. Systolic BP did not differ during step 1 of the warm-up (141 ± 15 vs. 137 ± 12 mmHg, P = 0.39) but was lower following PSD during step 2 (165 ± 21 vs. 159 ± 22 mmHg, P = 0.004) and the 20-min time trial (171 ± 20 vs. 164 ± 23 mmHg, P < 0.001). These results were maintained when peak oxygen uptake (V̇o_2peak) was included as a covariate. Systolic BP responses were modulated by sex (time × visit × sex interaction P = 0.03), with attenuated systolic BP during the warm-up and the 20-min time trial in males but not in females. In contrast to our hypothesis, acute PSD attenuates systolic BP responses during constant load and 20-min time trial cycling exercise; however, these observations appear to be primarily driven by changes in males.NEW & NOTEWORTHY A single night of partial sleep deprivation (PSD) can increase ambulatory blood pressure (BP) the following day. Despite this phenomenon, the present study found that acute PSD attenuates systolic BP responses to both constant load cycling and a 20-min cycling time trial in young healthy adults. Interestingly, the attenuated systolic BP responses following PSD appeared to be modulated by sex such that attenuations were observed in males but not in females.

Thoracic aortic aneurysm (TAA) is associated with Marfan syndrome (MFS), a connective tissue disorder caused by mutations in fibrillin-1. Sexual dimorphism has been recorded for TAA outcomes in MFS, but detailed studies on the differences in TAA progression in males and females and their relationships to outcomes have not been performed. The aims of this study were to determine sex differences in the diameter dilatation, mechanical properties, and extracellular matrix (ECM) remodeling over time in a severe mouse model (Fbn1^mgR/mgR = MU) of MFS-associated TAA that has a shortened life span. Male and female MU and wildtype (WT) mice were used at 1-4 mo of age. Blood pressure and in vivo diameters of the ascending thoracic aorta were recorded using a tail-cuff system and ultrasound imaging, respectively. Ex vivo mechanics and ECM remodeling of the aorta were characterized using a biaxial test system and multiphoton imaging, respectively. We showed that mechanical properties, such as structural and material stiffness, and ECM remodeling, such as elastic and collagen fiber content, correlated with diameter dilatation during TAA progression. Male MU mice had accelerated rates of diameter dilatation, stiffening, and ECM remodeling compared with female MU mice which may have contributed to their decreased life span. The correlation of mechanical properties and ECM remodeling with diameter dilatation suggests that they may be useful biomarkers for TAA progression. The differences in diameter dilatation and life spans in male and female MU mice indicate that sex is an important consideration for managing thoracic aortic aneurysm in MFS. NEW & NOTEWORTHY Using a mouse model (Fbn1^mgR/mgR = MU) of severe thoracic aortic aneurysm in Marfan syndrome (MFS), we found that male MU aorta had an accelerated time line and increased amounts of dilatation, stiffening, and extracellular matrix (ECM) remodeling compared with female MU aorta that may have contributed to an increased risk of fatigue failure with cyclic loading over time and a reduced life span. We suggest that aortic stiffness may provide useful information for clinical management of aneurysms in MFS.

Cardiogenic shock (CS) is characterized by impaired cardiac function, very high mortality, and limited treatment options. The proinflammatory signaling during different phases of CS is incompletely understood. We collected serum and plasma (n = 44) as well as freshly isolated peripheral blood mononuclear cells (PBMCs, n = 7) of patients with CS complicating acute myocardial infarction on admission and after revascularization (24, 48, and 72 h) and of healthy controls (serum and plasma, n = 75; PBMCs, n = 12). PBMCs of patients with CS had increased gene expression of NLRP3, CASP1, PYCARD, IL1B, and IL18 and showed increased rates of pyroptosis (control, 4.7 ± 0.3 vs. 9.9 ± 1.7% in patients with CS, P = 0.02). Serum interleukin (IL)-1β levels were increased after revascularization. IL-18 and IL-6 were higher in patients with CS than in healthy controls but comparable before and after revascularization. Proinflammatory apoptosis-associated speck-like proteins containing CARD (ASC) specks were elevated in the serum of patients with CS on admission and increased after revascularization (admission, 11.1 ± 4.4 specks/µL; after 24 h, 19.0 ± 3.9, P = 0.02). ASC specks showed a significant association with 30-day mortality in patients with CS (P < 0.05). The estimated regression coefficients and odds ratios indicated a positive relationship between ASC specks and mortality (odds ratio: 1.029, 95% confidence interval, 1.000 to 1.072; P = 0.02). Pyroptosis and circulating ASC specks are increased in patients with CS and are particularly induced after reperfusion. This underscores their potential role as a biomarker for poor outcomes in patients with CS. ASC specks represent promising new therapeutic targets for patients with CS with high inflammatory burden.NEW & NOTEWORTHY The expression of NLR family pyrin domain containing-3 (NLRP3) inflammasome-related genes and the rate of pyroptosis are increased in PBMCs from patients with CS. Furthermore, patients with CS are characterized by higher serum concentrations of ASC specks and IL-1β, IL-6, and IL-18. This current study adds circulating ASC specks to the portfolio of biomarkers for the identification of patients with a high inflammatory burden paving the way for precision medicine approaches to improve clinical outcomes.

Peripheral microvascular dysfunction has been documented in patients with heart failure with preserved ejection fraction (HFpEF), which may be related to elevated levels of inflammation and oxidative stress. Unfortunately, few strategies have been identified to effectively ameliorate this disease-related derangement. Thus, using a parallel, double-blind, placebo-controlled design, this study evaluated the efficacy of 30-day atorvastatin administration (10 mg daily) on lower limb microvascular reactivity, functional capacity, and biomarkers of inflammation and oxidative stress in patients with HFpEF (statin, n = 8, 76 ± 6 yr; placebo, n = 8, 68 ± 9 yr). The passive limb movement (PLM)-induced hyperemic response and 6-min walk test (6MWT) distance were evaluated to assess ambulatory muscle microvascular function and functional capacity, respectively. Circulating biomarkers were also measured to assess the contribution of changes in inflammation and redox balance to these outcomes. The total hyperemic response to PLM, assessed as leg blood flow area under the curve (LBF_AUC), increased following the statin intervention (pre, 60 ± 68 mL; post, 164 ± 90 mL; P < 0.01), whereas these variables were unchanged in the placebo group (P = 0.99). There were no significant differences in 6MWT distance following statin or placebo intervention. Malondialdehyde (MDA), a marker of lipid peroxidation, was significantly reduced following the statin intervention (pre, 0.68 ± 0.10; post, 0.51 ± 0.11; P < 0.01) while other circulating biomarkers were unchanged. Together, these data provide new evidence for the efficacy of low-dose statin administration to improve locomotor muscle microvascular reactivity in patients with HFpEF, which may be due, in part, to a diminution in oxidative stress.NEW & NOTEWORTHY This was the first study to investigate the impact of statin administration on locomotor muscle microvascular function in patients with HFpEF. In support of our hypothesis, the total hyperemic response to PLM, assessed as leg blood flow area under the curve, increased, and malondialdehyde, a marker of oxidative damage, was reduced following the statin intervention. Together, these data provide new evidence for the efficacy of statin administration to improve locomotor muscle microvascular reactivity in patients with HFpEF, which may be due, in part, to reduced oxidative stress.

Obesity is associated with excess lipid deposition in nonadipose tissues, leading to increased oxidative stress and insulin resistance. Very low-density lipoprotein receptor (VLDLR), a member of the LDL receptor family, binds and increases the catabolism of triglyceride-rich lipoproteins. Although VLDLR is highly expressed in the heart, its role in obesity-associated oxidative stress and insulin resistance is unclear. Here, we used lean (wild type), genetically obese leptin-deficient (ob/ob), and leptin-VLDLR double-null (ob/ob-VLDLR^-/-) mice to determine the impact of VLDLR deficiency on obesity-induced oxidative stress and insulin resistance in the heart. Although insulin sensitivity and glucose uptake were reduced in the hearts of ob/ob mice, VLDLR expression was upregulated and was associated with increased VLDL uptake and excess lipid deposition. This was accompanied by an upregulation of cardiac NADPH oxidase (Nox) expression and increased production of Nox-dependent superoxides. Silencing the VLDLR in ob/ob mice had reduced VLDL uptake and prevented excess lipid deposition in the heart, in addition to a reduction of superoxide overproduction and the normalization of insulin sensitivity and glucose uptake. In isolated cardiomyocytes, VLDLR deficiency had prevented VLDL-mediated induction of Nox activity and superoxide overproduction while improving insulin sensitivity and glucose uptake. Our findings indicate that VLDLR deficiency prevents excess lipid accumulation and moderates oxidative stress and insulin resistance in the hearts of obese mice. This effect is linked to the active role of VLDLR in VLDL uptake, which triggers a cascade of events leading to increased Nox activity, superoxide overproduction, and insulin resistance.NEW & NOTEWORTHY Obesity is associated with excess lipid deposition in muscles, which is considered as a leading cause of metabolic dysfunction and oxidative stress. Cellular uptake of lipids is regulated by several membrane receptors, among which is the very low-density lipoprotein receptor (VLDLR). This article provides information on the role of VLDLR in cardiac muscle and how its expression regulates insulin resistance and oxidative stress in the obese mouse model.

Atherosclerosis is commonly known as an inflammatory disease that is characterized by lipid deposition in the arterial wall, causing gradual restriction or complete blockade of blood flow, which can cause complications such as myocardial infarction, stroke, or peripheral artery disease. Several factors contribute to initiation and progression of atherosclerotic plaque formation. The role of macrophages and leukocytes in atherosclerosis has been well explored. Here, we provide an overview of what has been reported on the role and impact of the arterial cells on plaque formation, and vice versa. The atherogenic environment can trigger transformation and dedifferentiation of the endothelial cells (ECs), smooth muscle cells, and fibroblasts (FBs) whereby they can either directly contribute to plaque formation or influence its composition. Recent studies have demonstrated the plasticity in the identity of the arterial cells, the formation of intermediate cell types that share the characteristics of multiple cell types, and have revealed novel roles and functions for these cells in atherosclerosis. The potential for all vascular cells to cross-transdifferentiate, and detection of cells with mosaic characteristics in the atherosclerotic plaques reveal that the plaque environment is a complex and dynamic environment that could regulate the disease progression independent from the circulating lipid levels. We will also provide an overview on the interplay between sex and atherosclerosis, which has remained an underexplored area.

Scn1b plays essential roles in the heart, where it encodes β₁-subunits that serve as modifiers of gene expression, cell surface channel activity, and cardiac conductivity. Reduced β₁ function is linked to electrical instability in various diseases with cardiac manifestations and increased susceptibility to arrhythmias. Recently, we demonstrated that loss of Scn1b in mice leads to compromised mitochondria energetics and reactive oxygen species (ROS) production. In this study, we examined the link between increased ROS and arrhythmia susceptibility in Scn1b^-/- mice. In addition, ROS-scavenging capacity can be overwhelmed during prolonged oxidative stress, increasing arrhythmia susceptibility. Therefore, we isolated whole hearts and cardiomyocytes from Scn1b^-/- and Scn1b^+/+ mice and subjected them to an oxidative challenge with diamide, a glutathione oxidant. Next, we analyzed gene expression and activity of antioxidant enzymes in Scn1b^-/- hearts. Cells isolated from Scn1b^-/- hearts died faster and displayed higher rates of ROS accumulation preceding cell death compared with those from Scn1b^+/+. Furthermore, Scn1b^-/- hearts showed higher arrhythmia scores and spent less time free of arrhythmia. Lastly, we found that protein expression and enzymatic activity of glutathione peroxidase is increased in Scn1b^-/- hearts compared with wild type. Our results indicate that Scn1b^-/- mice have decreased capability to manage ROS during prolonged oxidative stress. ROS accumulation is elevated and appears to overwhelm ROS scavenging through the glutathione system. This imbalance creates the potential for altered cell energetics that may underlie increased susceptibility to arrhythmias or other adverse cardiac outcomes.NEW & NOTEWORTHY Using an oxidative challenge, we demonstrated that isolated cells from Scn1b^-/- mice are more susceptible to cell death and surges in reactive oxygen species accumulation. At the whole organ level, they were also more susceptible to the formation of cardiac arrhythmias. This may in part be due to changes to the glutathione antioxidant system.

Heart failure is a major cause of mortality following myocardial infarction. Neutrophils are among the first immune cells to accumulate in the infarcted region. While beneficial functions of neutrophils in heart injury are now appreciated, neutrophils are also well-known for their ability to exacerbate inflammation and promote tissue damage. Myocardial infarction induces hypoxia, where hypoxia-inducible factors (HIFs) are activated and play critical roles in cellular functions. In this context the role of Hif2α in neutrophils during myocardial infarction is unknown. Here, we reveal in experimental mice that neutrophil Hif2α deletion substantially attenuated myocardial infarction size, improved cardiac systolic function, and reduced survival and accumulation of tissue infiltrated neutrophils. Mechanistic studies revealed that Hif2α promotes neutrophil survival through binding to hypoxia response element in the promoter region of Birc2 to regulate expression of the pro-survival protein cellular inhibitor of apoptosis protein-1 (cIAP1). Inhibition of cIAP1 in neutrophils using the pharmacological agent, Birinapant resulted in increased cell death, establishing a critical role of cIAP1 downstream of Hif2α in neutrophil survival. Taken together, our data demonstrate a protective effect of Hif2α deletion in neutrophils on cardiac injury outcomes through modulation of neutrophil cell survival.