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

Prenatal hypoxia, a common pregnancy complication, can lead to vascular dysfunction, thereby increasing the risk of cardiovascular disease in the adult offspring. Carotid arteries are responsible for the majority of the blood flow to the brain/head, and carotid artery dysfunction is associated with life-threating cardiovascular events, such as stroke. However, whether prenatal hypoxia exposure impacts the function of the carotid arteries in the adult offspring is not known. We hypothesize that prenatal hypoxia impairs carotid artery function in the adult male and female offspring. Sprague Dawley rats were exposed to normoxia (21% O₂) or hypoxia (11% O₂) from gestational day (GD) 15 to 21 (term=22 days; n=9-11/group). Carotid arteries were isolated from the 4-month-old adult male and female offspring. Vasoconstrictor and vasodilatory properties were assessed by wire myography, and biomechanical properties (myogenic tone, circumferential stress and strain) by pressure myography. Collagen deposition (Masson's trichrome stain) and elastin density (Verhoeff stain) were measured in carotid artery cryosections. Prenatal hypoxia did not impact vasoconstriction or vasorelaxation responses in carotid arteries from both offspring. However, in males, prenatal hypoxia reduced carotid artery myogenic tone development and increased circumferential strain, which coincided with a lower collagen deposition and higher elastin density. In females, prenatal hypoxia tended to lower carotid artery circumferential strain (i.e., increased stiffness), without differences in myogenic tone or collagen/elastin density. Altogether, these data show that prenatal hypoxia exposure affects the carotid arteries of the adult offspring in a sex-specific manner, which may impact the blood flow regulation to the brain.

Pharmacologic beta-blockade is a well-established therapy for reducing adverse effects from sympathetic overactivity in cardiovascular diseases, such as heart failure. Despite decades of research efforts, in vivo cardiac functional studies utilizing genetic animal models remain scant. We generated a mouse model of cardiomyocyte-specific deletion of beta-1 adrenergic receptor (ADRB1) , the primary subtype expressed in cardiac myocytes, and demonstrated the role for ADRB1 in the maintenance of cardiac function at baseline and during exposure to increase in cardiac afterload by transient aortic occlusion and increasing heart rates (HRs) via atrial pacing. cKO hearts showed mildly depressed baseline left ventricular (LV) function, including slower HR, decreased contractility (dP/dtmax/IP) and prolonged relaxation (Tau) at baseline in both sexes. Exposure to increased LV afterload depressed LV function in either genotype similarly; however, the functional recovery following the removal of the afterload was severely impaired in cKO hearts, while cardiac function was immediately normalized in WT hearts. When HR was altered from 400 to 700bpm, cKO hearts were deficient in HR-dependent improvement of cardiac contractility and relaxation, known as positive force frequency relationship, that was evident in WT hearts. Enhanced phosphorylation of phospholamban by the HR increase was markedly blunted in cKO myocardium vs wild types, while CaMKII phosphorylation was comparable between the genotypes, suggesting the critical involvement of PKA. These results provide the first experimental evidence for the role of ADRB1 in cardiomyocytes for maintaining cardiac function at baseline and during acute stress, providing clinical perspective relating to the management of patients on beta-blockers.

Pathological left ventricular remodeling is a complex process following an acute myocardial infarction, leading to architectural disorganization of the cardiac tissue. This phenomenon is characterized by sterile inflammation and the exaggerated development of fibrotic tissue, which is non-contractile and poorly conductive, responsible for organ dysfunction and heart failure. At present, specific therapies are lacking for both prevention and treatment of this condition, and no biomarkers are currently validated to identify at-risk patients. Physiopathological understanding of this process is limited, probably due to the combination of the multi-cellular responses involved that are initially necessary for tissue healing but may be detrimental on longer term. Current research focuses on understanding and modulating the inflammatory response, a key aspect of the tissue healing process. Inflammation is triggered by the release of inflammatory mediators from cardiomyocytes undergoing cell death in the context of ischemia-reperfusion injury. Among them, extracellular ATP is a strong mediator of inflammation through the activation of P2 purinergic receptors, regulating the behavior of all the cellular actors of the post-myocardial infarction response and impacting organ function and recovery. Rather than considering each cellular protagonist independently, this review provides an integrated overview of the inflammatory and tissue response to myocardial infarction by members of the P2 receptor family. Finally, it explores the possibility of reducing pathological left ventricular remodeling through the modulation of these receptors and their associated signaling pathways.

The contribution of sex hormones to cardiovascular disease, including arterial stiffness, is established; however, the role of sex chromosome interaction with sex hormones, particularly in women, is lagging. Arterial structural stiffness depends on the intrinsic properties and transmural wall geometry that comprise a network of cells and extracellular matrix (ECM) proteins expressed in a sex-dependent manner. In this study, we used four-core genotype (FCG) mice to determine the relative contribution of sex hormones versus sex chromosomes or their interaction with arterial structural stiffness. Gonadal intact FCG mice included females (F) and males (M) with either XX or XY sex chromosomes (n=9-11/group). We isolated the thoracic aorta, and a tissue puller was used to assess structural resistance to changes in shape under control, collagenase, or elastase conditions. We determined histological collagen area fraction and evaluated aortic ECM genes by PCR microarrays followed by RT-qPCR. Stress-strain curves showed higher elastic modulus (P<0.001), denoting decreased extensibility in XXF compared to XYF aortas, which were significantly reversed by collagenase and elastase treatments (P<0.01). Aortic gene expression analysis indicated a significant reduction in Emilin1, Thbs2, and Icam1 in the XXF versus XYF aorta (P<0.05). Uniaxial stretching of XXF aortic vascular smooth muscle cells indicated decreased Thbs2, Ctnna1, and Ecm1 genes. We observed a significant (P<0.05) reduction in Masson's trichrome staining in collagenase but not elastase-treated aortic rings compared to the control. The increased aortic elastic modulus in XXF compared to XYF mice suggests a decrease in aortic extensibility mediated by a reduction in ECM genes.

This study investigated the sexual dimorphism in right ventricle (RV) remodeling in right heart failure susceptible Fischer CDF rats using the pulmonary artery banding (PAB) model. Echocardiography and hemodynamic measurements were performed in adult male and female Fischer CDF rats at 1- or 2-weeks post-PAB. RV systolic pressure and RV hypertrophy were significantly elevated in PAB rats compared to sham control at 1- and 2-weeks post-PAB; however, no differences were observed between male and female rats. Increase in cardiomyocyte cross-sectional area and RV end-diastolic diameter was observed in male rats compared to female rats at 2-weeks post-PAB. Conversely, higher fractional area change and cardiac index were observed in female rats compared to male rats at 2-weeks post-PAB. To explore the mechanisms, a focused PCR array was performed and higher expression of angiogenic genes, including sphingosine kinase-1 (Sphk1), was observed in the RV of female rats compared to male rats. Consistent with the higher angiogenic gene expression, female rats had a higher RV vascular density at 2-weeks post-PAB compared to male rats. Female RV endothelial cells (RVEC) had better angiogenic ability compared to male cells that was potentiated by estradiol. Furthermore, effect of estradiol on RVEC was inhibited by Sphk1 inhibitor (PF-543). Together, female Fischer CDF rats develop adaptive RV remodeling post-PAB compared to mal-adaptive remodeling in male rats. Moreover, the adaptive remodeling in female rats is associated with better RV angiogenic response that may result from better angiogenic ability of female RVEC and proangiogenic effects of estradiol through Sphk1.

Heart failure (HF) is a leading cause of death worldwide. We have shown that pressure overload (PO)-induced inflammatory cell recruitment leads to heart failure in IL-10 knockout (KO) mice. However, it's unclear if PO-induced inflammatory cells also target the gut mucosa, causing gut dysbiosis and leakage. We hypothesized that TAC (transverse aortic constriction) exacerbates immune cell homing to the gut (small intestine and colon), promoting dysbiosis and gut leakage in IL-10 KO mice. HF was induced in 8-10 weeks old C57BL/6J wild-type (WT) and B6.129P2-Il10tm1Cgn/J mutant (IL-10 KO) male and female mice by TAC and cardiac function was measured using visual sonics VEVO 3100. Fourteen days post-TAC, levels of monocytes, macrophages, neutrophils, and proinflammatory cytokines were measured in blood and gut. Gut dysbiosis was assessed via 16S rRNA sequencing in feces at 56 days post-TAC. IL-10 KO mice showed worsened cardiac dysfunction post-TAC. TAC worsened monocytes, and neutrophils infiltration in systemic circulation and facilitated their homing to the gut in IL-10 KO mice. Intriguingly, proinflammatory cytokines level was increased in blood, and gut of IL-10 KO mice following TAC. Furthermore, IL-10 expression was reduced in the colon of WT mice post-TAC. Moreover, TAC exacerbated gut dysbiosis in IL-10 KO mice. Finally, an impaired intestinal permeability was noted in IL-10 KO mice post-TAC. In conclusion, TAC-induced systemic inflammation leads to gut dysbiosis and impaired gut permeability in IL-10 KO mice, indicating IL-10's potential role in regulating intestinal integrity and microbiota balance during heart failure.

Cholinesterase (ChE) inhibitors are under consideration to be used in the treatment of cardiovascular pathologies. A prerequisite to advancing ChE inhibitors into the clinic is their thorough characterization in the heart. The aim here was to provide a detailed analysis of cardiac ChE to understand their molecular composition, localization, and physiological functions. A battery of biochemical, microscopic, and physiological experiments was used to analyze two known ChE, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), in hearts of mutant mice lacking different ChE molecular forms. Overall, AChE activity was exceeded by BChE, while it was localized mainly in the atria and the ventricular epicardium of the heart base. AChE was anchored by collagen Q (ColQ) in the basal lamina or by PRiMA at the plasma membrane and co-localized with the neuronal marker TUJ1. In absence of anchored AChE, heart rate was unresponsive to a ChE inhibitor. BChE, the major ChE in heart, was detected predominantly in ventricles, presumably as a precursor (soluble monomers/dimers). Mice lacking BChE were more sensitive to a ChE inhibitor. Nevertheless, the overall impact on heart physiology was subtle, showing mainly a role in cholinergic antagonism to the positive inotropic effect of β-adrenergic stimulation. Our results help to unravel the mechanisms of ChE in cardiovascular pathologies and provide a foundation to facilitate the design of novel, more effective pharmacotherapies, which may reduce morbidity and mortality of patients with various heart diseases.

Diabetes mellitus (DM) increases the risk of aortic stenosis (AS) and worsens its pathophysiology in a sex-specific manner. Aldosterone/mineralocorticoid receptor (Aldo/MR) pathway participates in early stages of AS and in other diabetic-related cardiovascular complications. We aim to identify new sex-specific Aldo/MR targets in AS complicated with DM. We performed discovery studies using Olink Proteomics® technology in 87 AS patient-derived aortic valves (AVs) (N=28 and N=19 non-diabetic and diabetic men; N=32 and N=8 non-diabetic and diabetic women, respectively) and human cytokine array (N=24 AVs/sex/condition). Both approaches revealed chemerin as a target differentially upregulated in AVs from male diabetic patients, further validated in a cohort of stenotic AVs (N=283, 27.6% DM, 59.4% men). Valvular chemerin levels directly correlated with VIC activation, MR, inflammation, angiogenesis and calcification markers exclusively in diabetic men. In vitro, Aldo (10^-8M) treatment exclusively increased chemerin levels in valve interstitial cells (VICs) from male DM patients. Aldo also upregulated inflammatory, angiogenic and osteogenic markers in DM and non-DM donors' VICs, which were prevented by MR antagonism. Increased glucose levels in cell media upregulated chemerin in VICs from male diabetic patients. Overall, RARRES2-knockdown in male diabetic VICs resulted in downregulation of inflammatory, angiogenic and osteogenic markers and blocked Aldo-induced responses in high glucose conditions. These data suggest the Aldo/MR pathway selectively increases chemerin in VICs from diabetic men, promoting inflammation, angiogenesis and calcification associated to AS progression.

Background: Aortic regurgitation (AR) is more prevalent in male, although cellular and molecular mechanisms underlying the sex differences in prevalence and pathophysiology are unknown. Objectives: This study evaluates the impact of sex on aortic valve (AV) inflammation and remodeling as well as the cellular differences in valvular interstitial cells (VICs) and valvular endothelial cells (VECs) in patients with AR. Methods: A total of 144 patients (27.5% female) with severe chronic AR were included. AVs were analyzed by imaging, histological and molecular biology techniques (ELISA, RT-PCR). VICs and VECs isolated from patients with AR were characterized and further treated with transforming growth factor (TGF)-β. Results: Anatomically, male had smaller index aortic dimensions and greater AV thickness. Proteome profiler analyzes in AVs (n=40/sex) evidenced higher expression of inflammatory markers in male and that was further validated (interleukins, chemokines). Histological composition showed higher expression of inflammatory mediators and collagen thick fibers in AVs from male. Male VICs and VECs secreted higher levels of inflammatory markers than female cells. Interestingly, male VICs produced higher amounts of collagen type I and lower fibronectin and aggrecan, whereas male VECs secreted lower decorin. TGF-β exclusively enhanced inflammation in male VICs, and decorin and aggrecan in female VICs. Conclusion: Compared to male, AVs from female were thinner, less inflamed and fibrotic. VIC seem to be the key cell type responsible for the sex-differences. Valvular inflammation associated with an active remodeling process could be a key pathophysiological process involved in AR.