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

Tissue sodium accumulation affects cardiovascular pathophysiology; however, current tissue element trace determination methods show high variability, limiting translational studies. We evaluated within-sample variability and tested whether microwave digestion reduced variability compared with dry ashing and whether flame atomic emission spectrometry (FAES) reduces variability compared with inductively coupled plasma-optical emission spectrometry (ICP-OES). Skin and muscle samples from rats, mice, and humans were divided into three parts and digested separately. Within-subject variability was tested by repeating the microwave digestion workflow on the second and third tissue pieces. Certified reference material (CRM) was used to assess recovery. Agreement between digestion and detection techniques was assessed using Bland-Altman analysis and intraclass correlation coefficients (ICCs). Interassay CVs for the microwave digestion/FAES workflow were 3.3 ± 2.8% for water, 9.1 ± 8.5% for sodium, and 14.9 ± 12.1% for potassium. CRM recovery was 98.9% for sodium and 91.5% for potassium. Dry ashing and microwave digestion agreement was good for sodium (ICC = 0.78) and excellent for potassium (ICC = 0.91). The dry ashing quantified less sodium than microwave digestion (-2.3 ± 23.7%), correlating to tissue weight (r = 0.54, P < 0.001) and negatively to sodium concentration (r = -0.63, P < 0.001). ICP-OES and FAES displayed excellent agreement for both elements (ICC > 0.90). The use of dry ashing and intrasample composition emerged as the primary driver of variability. Microwave digestion reduces variability and bias relative to dry ashing, whereas FAES maintained analytical concordance with ICP-OES, enabling more reproducible, faster, and easier quantification of tissue sodium and potassium in human and rodent studies relevant to cardiovascular physiology.NEW & NOTEWORTHY Tissue sodium is increasingly linked to cardiovascular pathophysiology, yet current measurement methods are slow, costly, and inconsistent. In this study, we quantified the variability of sodium and potassium assessment across human and rodent tissues. We show that ashing contributes to measurement bias, whereas microwave digestion offers a faster, more reproducible, and accessible workflow compared with dry ashing. This approach enables standardized electrolyte analysis to advance cardiovascular research.

MicroRNAs (miRNAs), short noncoding RNAs that posttranscriptionally regulate gene expression, have emerged as critical regulators of cardiac genes. Although circulating miRNAs have been implicated in cardiovascular disease, their precise functional roles remain poorly understood. Using Drosophila as a model, we applied miRNA sponge technology to competitively inhibit miR-6 (the mammalian homolog, miR-27), enabling us to systematically assess its impact on heart function, morphology, and lifespan. Functional and structural cardiac changes were analyzed with semiautomatic optical heartbeat analysis (SOHA) software and immunohistochemistry. In silico target analysis revealed 149 conserved predicted gene targets shared by this miRNA family, highlighting its potential regulatory scope. Our findings uncover a novel cardioprotective role for miR-6 inhibition, demonstrating that heart-specific miR-6 suppression mitigates age-related changes to heart size and function, significantly extends lifespan, and leads to increased lipid accumulation in cardiomyocytes. Importantly, we observed elevated expression of the conserved target gene low-density lipoprotein receptor-related protein 1 (LRP1) in miR-6-inhibited hearts, and genetic disruption of LRP1 expression in miR-6 inhibition decreased lipid accumulation in the heart. Conservation of miR-27b and LRP1B expression in mammalian cardiac tissue further validates the translational relevance of these findings.NEW & NOTEWORTHY This work establishes miR-6 as a novel regulator of cardiac health, specifically in aging, through its modulation of lipid metabolism, heart function, and longevity. These insights expand our understanding of miRNA-mediated cardiac regulation and provide a foundation for developing miRNA-targeted therapies to combat heart disease and age-related cardiac decline.

Angiogenesis, the formation of new blood vessels from pre-existing ones, is essential for development, tissue repair, and tumorigenesis. As a delicately orchestrated morphogenesis process, angiogenesis is driven by endothelial cell (EC) migration and proliferation in response to environmental signals such as angiogenic factors. Both the environmental signals from non-ECs and their corresponding receptors and downstream pathways in ECs are key for angiogenesis. RNA-binding proteins (RBPs) play a critical role in regulating gene expression posttranscriptionally. Their complex interactions with RNA molecules determine RNA fate, ultimately influencing protein expression and cell behavior. Although RBPs' regulation of gene expression at the posttranscriptional level is relatively understudied in vascular biology, recent studies highlight their significance in modulating angiogenic gene pathways in both ECs and non-ECs. This review summarizes recent findings and identifies knowledge gaps regarding the roles of RBPs in recognizing and regulating both canonical mRNAs and chemically modified mRNAs during angiogenesis, with a focus on molecular mechanisms of how RBPs regulate their target mRNAs.

Exercise training has been shown to reverse cardiac dysfunction in patients and animal models of coronary artery disease; however, the underlying mechanisms have not been fully elucidated. Transmembrane integrins that connect the extracellular matrix (ECM) and intracellular cytoskeleton are important for mechanotransduction in cardiomyocytes. We tested the hypothesis that exercise training would increase cardiac contractile function by modulating the adhesion force between integrins and ECM proteins and subsequent cell signaling and stiffness in myocytes from ischemic porcine hearts. Ameroid occluders were surgically placed around the proximal left circumflex coronary artery of adult Yucatan pigs. Animals subsequently completed either a sedentary or endurance exercise (treadmill run 5 days/wk for 14 wk) protocol, after which myocardium was isolated from nonoccluded and collateral-dependent regions. The collateral-dependent myocardial region exhibited increased fibrosis, inflammatory cytokines, and collagen I and III levels, which were ameliorated with exercise training. Exercise also increased fibronectin and β1 integrin and decreased β3 integrin levels in collateral-dependent myocardium compared with that of sedentary pigs. Atomic force microscopy revealed that an increase in fibronectin-integrin adhesion force was mediated by α₅β₁ and α_vβ₃ integrins in cardiac myocytes of exercise-trained pigs. Exercise training increased mechanical stiffness in cardiomyocytes compared with that in sedentary swine. Fibronectin- and exercise-induced force generation in trabeculae from collateral-dependent myocardium was each decreased by focal adhesion kinase (FAK) inhibition. These data demonstrate that exercise training increases force generation in cardiomyocytes by attenuating inflammation and by promoting fibronectin-mediated FAK activation, suggesting potential targeting of this mechanotransduction pathway for therapeutic development.NEW & NOTEWORTHY Exercise produces cardioprotective effects and reverses cardiac dysfunction, but underlying cellular and molecular mechanisms are not fully identified. This study revealed that endurance exercise increased fibronectin expression in the myocardium of ischemic swine hearts and enhanced myocyte adhesion with α₅β₁ integrin, cell stiffness, and force generation, which was blunted by focal adhesion kinase inhibition. Thus, endurance exercise reverses cardiac dysfunction by promoting fibronectin interactions with integrins supporting this mechanotransduction pathway as a potential therapeutic target.

Dilated cardiomyopathy (DCM), characterized by left ventricular dilation and systolic dysfunction, remains a major cause of heart failure, necessitating improved diagnostic strategies. Conventional imaging techniques such as echocardiography and MRI, along with classical cardiovascular markers like NT-proBNP and cTnT, demonstrate limited sensitivity for DCM-specific phenotypes. Given the critical role of lipids and proteins in cardiac physiology, their alteration may provide disease-specific diagnostic insights. To address the scarcity of comprehensive lipidomic studies and validated protein biomarkers in DCM, we used a high-resolution mass spectrometry-based integrative omics approach coupled with machine learning. Plasma samples from 360 participants, including patients with DCM and controls, were analyzed to identify specific proteolipidomic alterations. We detected 125 significantly altered lipids (0.8 ≥ FC ≥ 1.2; P_adj < 0.05) and 10 proteins, of which 39 lipids and 10 proteins were identified as primary discriminators using a Boruta-based ML approach. ELISA validation confirmed β2-microglobulin [β2micoglobulin (B2M); 6.85 ± 2.86 μg/mL vs. 4.26 ± 1.25 μg/mL; P < 0.0001] and tetranectin (CLEC3B; 1.99 ± 0.88 μg/mL vs. 2.49 ± 0.90 μg/mL; P = 0.0006) as significant protein biomarkers. Single-cell transcriptomic data from DCM myocardium supported these trends, showing cell type-specific alterations in B2M and CLEC3B expression. CLEC3B was positively correlated with phosphatidic acid (PA) (18:1/20:1), whereas oxidative stress marker 8-OHdG was markedly elevated in DCM plasma. Integrative receiver operating characteristic (ROC) analysis combining top lipid discriminators with B2M and CLEC3B achieved an area under the curve (AUC) of 0.99, surpassing NT-proBNP (0.96). Overall, this study delineates the first comprehensive proteolipidomic signature of DCM and proposes a robust multiparametric biomarker panel with enhanced diagnostic precision.NEW & NOTEWORTHY First study of global proteolipidomic changes in dilated cardiomyopathy (DCM). A machine-learning-guided biomarker pipeline identified 39 lipids and 10 proteins distinguishing DCM. We propose that PE (14:0/22:4), phosphatidic acid (PA) (18:1/20:1), and tetranectin (CLEC3B) may link oxidative stress, apoptosis, and ECM remodeling in DCM. A panel combining the top 8 lipid markers along with β2micoglobulin (B2M) and CLEC3B achieved an area under the curve (AUC) of 0.99, outperforming NT-proBNP and offering superior diagnostic accuracy.

Arterial pulse wave velocity (PWV), defined as the speed at which a blood pressure pulse propagates along the arterial tree, is the gold standard for assessment of arterial stiffness and can serve as an independent predictor of cardiovascular events, such as myocardial infarction, stroke, and heart failure. However, recent animal data suggest that pulse wave velocity measurements may not only assess arterial stiffness but also highly dynamic changes in local homeostasis and the delicate artery whole body interplay. This narrative review summarizes the major contributing factors to changes in pulse wave velocity and proposes novel classification into these factors as being either intrinsic or extrinsic to the vasculature. Intrinsic factors known to modulate pulse wave velocity include the elastin, collagen and calcium content of the arterial wall, smooth muscle tone, and endothelial cell function. In contrast, extrinsic factors include variables such as sex, and others that can fluctuate such as blood pressure, heart rate, metabolic health, and age. We highlight how increases in pulse wave velocity may be variable and oversimplified depictions of aortic stiffness and suggest that they are holistic measurements of vascular hemodynamic stress that also include the cumulative impact of mechanical forces, biochemical alterations, and structural and/or functional changes to the vasculature.

The capacity of the endothelium to release tissue-type plasminogen activator (t-PA) is markedly impaired in adults with obesity, underlying their increased thrombotic risk. Circulating endothelial cell-derived microvesicles (EMVs) are systemic modulators of vascular health and disease, and are elevated with obesity. The experimental aim of this study was to determine whether circulating EMVs are associated with obesity-related endothelial fibrinolytic dysfunction. Twenty-eight sedentary, midlife and older adults (45-71 yr) were studied: 14 normal-weight (7 M/7 F; age: 55 ± 4 yr; body mass index: 23.1 ± 1.6 kg/m²) adults and 14 adults with obesity (7 M/7 F; 57 ± 8 yr; 31.9 ± 2.9 kg/m²). EMV identification (CD144⁺) and concentration in peripheral blood were determined by flow cytometry. Endothelial release of t-PA was determined, in vivo, in response to intrabrachial infusions of bradykinin (BK: 125-500 ng/min) and sodium nitroprusside (SNP: 2.0-8.0 µg/min). Circulating EMV levels were ∼170% higher (P < 0.001) in adults with obesity (183 ± 58 EMV/µL) compared with normal-weight (68 ± 12 EMV/µL) adults. Endothelial t-PA release in response to BK was significantly lower (∼30%) in the adults with obesity (from 0.7 ± 3.6 to 35.9 ± 15.1 ng/100 mL tissue/min) versus normal-weight adults (-0.5 ± 2.3 to 68.4 ± 21.1 ng/100 mL tissue/min). Consequently, total t-PA release (area under the BK curve) was lower (∼35%; P = 0.007) in the adults with obesity (205 ± 118 ng/100 mL tissue vs. 325 ± 97 ng/100 mL tissue). Circulating EMVs were significantly and inversely associated with both peak t-PA release (r = -0.67; P = 0.0001) and total t-PA release to BK (r = -0.53; P = 0.004). In summary, obesity-related increase in circulating EMVs is associated with diminished endothelial t-PA release. Circulating EMVs may serve as a biomarker of fibrinolytic dysfunction in adults with obesity.NEW & NOTEWORTHY Obesity is associated with profound impairment in the capacity of the vascular endothelium to release tissue-type plasminogen activator (t-PA), the primary mechanism underlying endogenous thrombolysis. Circulating endothelial cell-derived extracellular vesicles (EMVs) have been linked to endothelial dysfunction. This study demonstrates that circulating EMVs are elevated in adults with obesity and are associated with reduced endothelial t-PA release. Circulating EMVs represent a novel systemic biomarker of obesity-related endothelial fibrinolytic dysfunction and, in turn, thrombotic risk.

Sigma receptor agonists are suspected to modulate blood pressure in humans. We investigated how modulation of sigma receptors impacts phenylephrine (PE)-induced contraction in human mesenteric arterial rings obtained from human organ donors. This study also explored the relationship between sigma receptor activation, PE-induced arterial contraction, and the history of the organ donor's alcohol use. The concentration responsiveness of PE-induced arterial contraction was tested using wire myography in the absence and presence of the sigma receptor agonist PRE-084, and the sigma receptor antagonists BD-1047 and SM-21. Sigma receptor-1 expression in the arteries was also investigated using an automated capillary electrophoresis system. The results show that PRE-084 elicited a downward shift in the PE concentration-response curve. Notably, this trend only occurred in arteries from donors with histories of non-/light drinking or moderate drinking (P < 0.05) but not with arteries obtained from donors with histories of heavy or binge drinking. The sigma receptor-1 antagonist BD-1047 elicited an upward shift in the PE concentration-response curve in arteries from non-/light and moderate drinkers but not from heavy drinkers. Interestingly, the sigma receptor-2 antagonist caused an upward shift in the PE concentration-response curve in arteries from all three groups of donors. Notably, sigma receptor-1 protein levels were decreased in arteries from heavy drinkers compared with the other groups. Collectively, the findings suggest that sigma receptors in human arteries may promote relaxation. However, heavy alcohol consumption reduces arterial sigma receptor-1 expression and impairs its ability to modulate contraction.NEW & NOTEWORTHY Activation or inhibition of sigma receptor-1 was found to modulate phenylephrine-induced contraction of isolated mesenteric arteries from human organ donors. However, this effect was impaired in arteries from donors who were heavy alcohol consumers, because the arteries from these individuals had relatively low protein expression of sigma receptor-1. These findings reveal a potential new role of sigma receptor-1 in the control of arterial tone in humans that is modulated by alcohol use.