Regulation Of Cardiovascular Function Research Articles

Prenatal dexamethasone programs autonomic dysregulation in female rats.

Autonomic dysfunction is associated with cardiovascular and neurological diseases, including hypertension, heart failure, anxiety, and stress-related disorders. Prior studies demonstrated that late gestation exposure to dexamethasone (DEX) resulted in female-biased increases in stress-responsive mean arterial pressure (MAP) and heart rate (HR), suggesting a role for glucocorticoid-mediated programming of autonomic dysfunction. The present study investigated the influence of sympathetic (SYM) or parasympathetic (PS) blockade on cardiovascular function in male and female rat offspring of mothers injected with DEX in utero [gestation days (GD) 18-21]. At 11-12-wk of age, MAP, HR, and heart rate variability (HRV) were evaluated at baseline and in response to SYM antagonists (α1-adrenoceptor + β1-adrenoceptor), a PS (muscarinic) antagonist, or saline (SAL). To assess stress-responsive function, rats were exposed to acute restraint. Tyrosine hydroxylase was measured in the adrenals and left ventricle, and expression of the β1 adrenergic receptor, choline acetyltransferase, and acetylcholinesterase were measured in the left ventricle. Maternal DEX injection reduced basal HRV in male and female offspring. SYM blockade attenuated increases in stress-responsive HR and MAP. PS blockade elevated stress-responsive HR and MAP to a greater extent in vehicle females. SYM and PS blockade produced equivalent effects on HR and MAP responses in male offspring, regardless of maternal treatment. Based on these findings, we suggest that maternal DEX injection disrupted autonomic regulation of cardiovascular function in females, resulting in a shift toward greater SYM input and less input from PS. Future studies will investigate whether changes in autonomic function are mediated by changes in central autonomic circuitry.NEW & NOTEWORTHY Pharmacological antagonists are used to characterize the nature of the autonomic dysregulation induced in female offspring exposed to dexamethasone, in utero. The female offspring of dams injected with dexamethasone in late gestation show a reduction in vulnerability to parasympathetic blockade and an increase in responses to acute restraint stress even in the presence of sympathetic blockade. This suggests that late gestation dexamethasone disrupts the normal development of the autonomic function in females, shifting sympathovagal balance.

From physiology to pathology: Emerging roles of GPER in cardiovascular disease.

Cardiovascular diseases (CVDs) are among the leading causes of death globally and pose a significant threat to public health. Factors such as prolonged high cholesterol levels, diabetes, smoking, unhealthy diet, and genetic predisposition could contribute to the occurrence and development of CVDs. Common CVDs include hypertension (HTN), atherosclerosis (AS), myocardial infarction (MI), myocardial ischemia-reperfusion injury (MIRI), heart failure (HF) and arrhythmia. Estrogen is recognized for its cardiovascular protective effects, resulting in lower incidence and mortality rates of CVDs in premenopausal women compared to men. The G protein-coupled estrogen receptor (GPER), a G protein-coupled receptor with a seven-transmembrane structure, exhibits unique structural characteristics and widespread tissue distribution. GPER activates intracellular signaling pathways through its interaction with G proteins, mediating estrogen's biological effects and participating in the regulation of cardiovascular function, metabolic balance, and nervous system. Although recent research has highlighted the significant role of GPER in the cardiovascular system, its specific mechanisms remain unclear. Therefore, this review summarizes the latest research on GPER in CVDs, including its fundamental characteristics, physiological functions in the cardiovascular system, and its roles and potential therapeutic applications in common CVDs such as HTN, AS, MI, MIRI, HF and arrhythmia. Exploring GPER's positive effects on cardiovascular health will provide new strategies and research directions for the treatment of CVDs.

The Effect of Non-Invasive, Non-Pharmacological Interventions on Autonomic Regulation of Cardiovascular Function in Adults with Spinal Cord Injury: A Systematic Review with Meta-Analysis

The Effect of Non-Invasive, Non-Pharmacological Interventions on Autonomic Regulation of Cardiovascular Function in Adults with Spinal Cord Injury: A Systematic Review with Meta-Analysis

Elabela alleviates cuproptosis and vascular calcification in vitaminD3- overloaded mice via regulation of the PPAR-γ /FDX1 signaling

BackgroundVascular calcification is a crucial pathophysiological process associated with age-related cardiovascular diseases. Elabela, a recently identified peptide, has emerged as a significant player in the regulation of cardiovascular function and homeostasis. However, the effects and underlying mechanisms of Elabela on age-related vascular calcification remain largely unexplored.MethodsIn-vivo vascular calcifications of C57BL/6J mice (8-week-old) and young (8-week-old) or aged (72-week-old) SD rats were injected with vitamin D3 (VitD3) or saline, respectively. Furthermore, the VitD3-overloaded mice received Elabela (1 mg/kg/d), peroxisome proliferators-activated receptor-γ (PPAR-γ) activator Rosiglitazone (5 mg/kg/d) or copper-ionophore Elesclomol (20 mg/kg/d), respectively. As for in-vitro studies, primary rat vascular smooth muscle cells (VSMCs) were isolated from aortas and cultured for explore the role and underlying mechanism of Elabela in vascular calcification.ResultsThere were marked increases in FDX1 and Slc31a1 levels in both aortas and VSMCs during vascular calcification, coinciding with a rise in copper levels and a decrease in Elabela levels. Alizarin red and von-Kossa staining indicated that the administration of Elabela effectively hindered the progression of vascular cuproptosis and arterial calcification in VitD3-overloaded mice and rat arterial rings models. Moreover, Elabela significantly suppressed osteogenic differentiation and calcium deposition in VSMCs and strikingly reversed high phosphate-induced augmentation of FDX1 expression, DLAT aggregation as well as intracellular copper ion levels. More importantly, Elabela exhibited remarkable abilities to prevent mitochondrial dysfunctions in primary rat VSMCs by maintaining mitochondrial membrane potential, inhibiting mitochondrial division, reducing mitochondrial ROS production and increasing ATP levels. Interestingly, Elabela mitigated cellular senescence and production of pro-inflammatory cytokines including IL-1α, IL-1β, IL-6, IL-18 and TNF-α, respectively. Furthermore, Elabela upregulated the protein levels of PPAR-γ in VitD3-overloaded mice. Administrating PPAR-γ inhibitor GW9662 or blocking the efflux of intracellular copper abolished the protective effect of Elabela on vascular calcification by enhancing levels of FDX1, Slc31a1, Runx2, and BMP2.ConclusionElabela plays a crucial role in protecting against vascular cuproptosis and arterial calcification by activating the PPAR-γ /FDX1 signaling. Elabela supplementation and cuproptosis suppression serve as effective therapeutic approaches for managing vascular calcification and related cardiovascular disorders.

Targeting the apelin axis: GPCR-directed peptide therapies for cardiovascular disease

Abstract. G protein-coupled receptors (GPCR)play key roles in various physiological processes, especially in the regulation of cardiovascular function and morphology. The current share of peptide- and protein-antibody-based GPCR drugs is gradually increasing. Several studies have identified and understood the role of GPCR in vasodilatory regulation and cardiac function. In addition, some studies have explored the relationship between GPCRs and CVD-related physiological processes such as inflammation, thrombosis and vascular endothelial function. There is still a gap in the study of GPCRs in CVD in terms of a deeper understanding of the role of specific subtypes of GPCRs in the pathological process and their signaling mechanims, as well as how to develop specific drugs targeting these receptors to improve therapeutic efficiency and reduce side effects. This article will focus on important signaling pathways related to CVD. The potential applications and research progress of drugs such as Apelin-13 and MM07 in CVD therapy are particularly emphasized. This paper provides a reference for future research on the progress of GPCR in CVD. Future studies could focus on in-depth exploration of the signaling pathways of GPCRs, the development of more specific and safe drugs, and the study of new strategies for GPCRs in the prevention and treatment of CVDs

Abstract 4136181: Automated Personalized Modulation of the Sympathetic “fight-or-flight” Reflex In Vivo Using Implantable Microdevices for Enhancing Neurocardiac Function and Reducing Mortality Risk.

Background: The sympathetic nervous system (SNS) is a critical regulator of cardiovascular function. Whereas acute SNS activation elicits positive inotropy and confers survival advantage, persistent SNS hyperactivity is maladaptive and can lead to arrhythmias, cardiac arrest and heart failure. Hypothesis: Automated optogenetic modulation of the sympathetic stress response in vivo enhances neurocardiac function while avoiding sympathetic hyperactivity-mediated pathological effects. Methods: In normal guinea pigs, we virally transduced excitatory and/or inhibitory channelrhodopsins to the stellate ganglia (SG), the primary sympathetic input to the heart. We studied in situ effects of graded activation of SG opsins (e.g., phasic vs tonic) on cardiac function (e.g., ECG, heart rate) with and without perfusing agents (e.g., β-blockers, antioxidants). In vivo studies used novel implanted µLED devices for wireless body signal streaming (e.g., ECG) and neurophotonic SG opsin modulation closed-loop to dynamic analyses of physiological demand versus ECG-based cardiac risk prediction. Results: Compared to baseline heart rate (218±16 bpm), pulsed activation of inhibitory opsins reduced heart rate by ~25% (156±12; delta=67±14 bpm; p<0.0003; N=5). Pulsed activation of excitatory opsins increased heart rate by ~30% (285±28; delta=65±19 bpm; p<0.0002; N=5). Interestingly, prolonged (>20 min) tonic excitation of the SG caused desensitization, possibly as an intrinsic safety mechanism. Whereas graded SG excitation or inhibition at different LED intensities elicited prompt changes in heart rate, repeated activation of excitatory opsins led to quick desensitization. Our ongoing studies are aimed at understanding how and when SG modulation can enhance cardiac function, trigger intrinsic cardioprotective mechanisms, or cause pathological effects. Conclusion: Automated neurophotonic optogenetic excitation or inhibition of the SG is a robust personalized strategy for modulating cardiovascular function. The ability to rapidly and accurately modulate the sympathetic stress reflex in a graded manner can lead to more timely, effective, and appropriate physiological responses while avoiding undesired pathophysiological responses.

Neuroimmune modulation for targeting organ damage in hypertension and atherosclerosis.

The brain is essential for processing and integrating sensory signals coming from peripheral tissues. Conversely, the autonomic nervous system regulated by brain centres modulates the immune responses involved in the genesis and progression of cardiovascular diseases. Understanding the pathophysiological bases of this relationship established between the brain and immune system is relevant for advancing therapies. An additional mechanism involved in the regulation of cardiovascular function is provided by the brain-mediated control of the renin-angiotensin system. In both cases, the communication is typically bidirectional and established by afferent and sensory signals collected at the level of peripheral tissues, efferent circuits, as well as of hormones. Understanding how the brain mediates the bidirectional communication and how the immune system participates in this process is object of intense investigation. This review examines key findings that support a role for these interactions in the pathogenesis of major vascular diseases that are characterized by a consistent alteration of the immune response, such as hypertension and atherosclerosis. In addition, we provide a critical appraisal of the translational implications that these discoveries have in the clinical setting where an effective management of neuroimmune and/or neuroinflammatory state might be beneficial.

Abstract P431: Crosstalk Between Dopamine Receptors and AT1R in Hypertension Induced Cardiac Remodeling

Dopamine receptors are implicated in the regulation of cardiovascular function, yet their specific roles in the modulation of hypertension and cardiac remodeling are not fully understood. The angiotensin II type 1 receptor (AT1R) plays a critical role in the pathophysiology of hypertension by mediating vasoconstriction, sodium retention, and sympathetic nervous system activation. Previous studies from our lab have demonstrated that in Ang II-induced hypertension, there are alterations in D1R and D3R expression in the left ventricle (LV) compared to wild-type (WT) mice. Evidence indicates that AT1R and D1R form heterodimers and inhibition of AT1R has been shown to enhance D1R signaling in proximal tubules, suggesting a significant interaction between these receptor systems. However, the role of intracardiac dopamine receptors on AT1R expression during hypertension remains understudied. Therefore, this study aims to elucidate the crosstalk between intracardiac dopamine receptors and AT1R in the context of hypertension and cardiac remodeling by using in vitro and in vivo pharmacological and molecular methods combined with novel genetic models. Using global D3R deficient (D3KO) and WT mice, we observed that D3KO leads to alterations in AT1R gene expression in LV compared to WT hearts (p<0.001) and in isolated LV cardiac fibroblasts (p<0.0001). D3KO and WT mouse cardiac fibroblasts (mCFb) and human cardiac fibroblasts (hCFb) were stimulated with Ang II (300nM) ± D1R antagonist (SCH, 10µM) or D3R antagonist (SB, 10µM). D1R antagonism significantly increased AT1R (Agtr1 gene) levels in both WT and D3KO mCFb (p<0.01), whereas D3R antagonism reduced AT1R gene expression following Ang II stimulation (p<0.01). Furthermore, these data were confirmed in hCFb. To determine crosstalk between dopamine receptors and AT1R, we used proximity ligation assay (PLA) to examine the close proximity (<40nm) of receptor-receptor expression and interaction. Our results indicate that in mCFb and hCFb, there is an increase in D1R-AT1R interactions following Ang II both with and without D1R antagonism (p<0.05), however, AT1R-D3R interactions were reduced (p<0.05). These data suggest that dopamine receptor activity significantly influences AT1R gene expression, highlighting a potential modulatory role for dopamine receptors in the regulation of AT1R during hypertension.

The level of adropin and von Willebrand factor in patients with arterial hypertension, excess body weight, and obesity

Objective. To investigate changes in adropin and von Willebrand factor (vWF) levels in patients with arterial hypertension (AH), excess body weight, and obesity.Material and methods. All patients were divided into two main groups: group 1 included 69 patients with AH and excess body weight; group 2 – 55 people with AH and obesity, and 20 healthy people of the control group. Anthropometric measurement, biochemical blood test, echocardiographic examination of the heart, and enzyme immunoassay (adropin, vWF) were performed.Results. The level of vWF was significantly higher in patients with AH, overweight, and obesity compared to healthy individuals (p=0,001). Meanwhile, the adropin level decreased with increasing BMI. The lowest adropin level was observed in individuals with AH and obesity (p=0,011). Additionally, a significant positive correlation was identified between vWF and the size of the LA (r=0,667; p=0,001), RV (r=0,487; p=0,021), MMLV (r=0,795; p=0,001) and IMMLV (r=0,731; p=0,001), whereas a negative correlation was found with EF (r=-0,461; p=0,031).Conclusions. An increase in vWF level was observed in patients with hypertension, overweight, and obesity which contributes to the emergence of endothelial dysfunction and structural myocardial changes, related to AH. The decrease in adropin level – a regulator of the cardiovascular system functions – was associated with an increase in BMI and elevated BP. Negative correlations were found between adropin and systolic and diastolic blood pressure values. It plays an important role in blood pressure and cardiovascular function regulation.

Mastication stimuli regulate the heartbeat rate through rhythmic regulation by the hypothalamic-autonomic system; molecular and telemetric studies in weaning-stage rats.

Mastication stimuli have been demonstrated to affect memory function and autonomic nerve activity; however, this process has not been well studied during weaning compared to old age. Previously, we conducted molecular analyses of the thalamus and hippocampus to elucidate the mechanisms underlying this memory-enhancing effect in weaning-stage rats. In this study, we aimed to evaluate the effect of masticatory stimuli on the regulation of heartbeat rate (HR) through the hypothalamic-autonomic system. Three-week-old male rats were administered a powdered diet (P group) or chow-diet (C group) for 10 days. Thereafter, transcriptome analysis was performed. Vasopressin, cocaine-amphetamine-regulated transcript prepropeptide, corticotropin-releasing hormone, and thyrotropin-releasing hormone, which are involved in sympathetic activation of heart rate, were downregulated in the C group. Electrocardiograms were recorded continuously for 12 days under the same condition. Interestingly, rats in the C group had a significantly lower HR than those in the P group on day 11. We checked several parameters representing the autonomic regulation of HR. The C group had higher values for the high-frequency band integration of the HR power spectrum (parasympathetic marker) and root mean square successive difference of R-wave intervals (parasympathetic marker) relative to the P group. Such findings provide a molecular and physiological basis for understanding the regulation of cardiovascular function in response to masticatory stimuli in the autonomic nervous system.

Abstract 088: Modulatory Effects Of The Gut Microbiota-derived Short Chain Fatty Acids On Heart Rate And Vascular Tone In Larval Zebrafish

Introduction: Short chain fatty acids (SCFAs), such as acetic, propionic, and butyric acid, areproduced by fermentation of dietary fibers by the gut bacteria. Deregulation in production andhandling of SCFAs is associated with cardiovascular dysfunction in humans and rodents.However, limited studies have investigated the effect of SCFAs on cardiovascular parameters inthe zebrafish (ZF), an increasingly popular model in cardiovascular and gut microbiota research. Methods: Bacterial 16s sequencing and GC-MS were performed in adult male and female Tg(NFkB:EGFP) ZF fecal samples for analysis of the gut microbiota and SCFAs respectively. Inanaesthetized ZF larvae (7-9 dpf; MS-222, 0.3mM), measurements of heart rate (HR, bpm) andvascular tone (width of dorsal aorta, pixels) were performed every 10 minutes for an hour usinglive imaging (Nikon, 4x magnification) following administration of physiologic concentrations ofacetate (27.4 μM), butyrate (2.2 μM) and propionate (1.7 μM; pH=7.5) via immersion. Results: Relative proportions of SCFAs in the ZF were similar to those previously reported in rats andhumans, with highest levels of acetic acid (27.43 μM) followed by butyric (2.19 μM) and propionic(1.65 μM) acid. At the phylum level, the observed abundances of Proteobacteria, Firmicutes, andFusobacteria were similar to those reported in rodents and humans. Administration of selectSCFAs resulted in a ~20% decrease in HR at all time points following administration of butyrate(P<0.0001), and at 40-60min following administration of acetate (P<0.05), with no effect ofpropionate. In addition, a ~25% decrease in the width of the dorsal aorta was observed at 60 minfollowing administration of butyrate (P<0.05), with no effect of acetate or propionate. Conclusion: We report a similar composition and abundances of the gut microbiota and SCFAs between ZF,rodents and humans. In addition, both butyrate and acetate produced a bradycardia in the ZF,while the observed butyrate-dependent decrease in the vascular tone may be compensatory tobradycardia. Our findings demonstrate the potential for ZF as a model to study host-microbiotainteractions in regulation of cardiovascular function.

Abstract P170: Beta-arrestin-2 Sustains Experience-dependent Plasticity Of Sodium Ingestive Behavior

Elevated sodium (Na) intake is a risk factor for hypertension. Na “appetite” is defined by the persistence of Na consumption despite adverse conditions and is commonly assessed through ingestion of aversive NaCl solutions. β-arrestins interact with many G Protein-Coupled Receptors (GPCR), including the Angiotensin II Type 1 Receptor (AT 1 R). β-arrestins play roles in many physiological processes including regulation of cardiovascular function, sensory processing, and energy metabolism. Recent work published by our group concluded that β-arrestin-2 deficient (Arrb2 KO ) mice exhibited increased ingestion of NaCl solutions even in the absence of physiological need. Thus, we hypothesize that β-arrestin-2 plays a role in experience-based Na seeking behavior and elevated NaCl consumption. To explore this question, mice were first presented with a 2-bottle choice of water and 0.15 NaCl.; then exposed to aversive 0.3 M NaCl exclusively for 24h; followed by the same 2-bottle choice as at baseline. Usually, this manipulation would yield a reduction in preference for previously preferred concentrations of NaCl, demonstrating experience-based plasticity of NaCl preference. At baseline, male Arrb2 KO mice exhibited the expected increase in preference for 0.15 M NaCl vs water (control n=14, 34±5%; Arrb2 KO n=10, 55±7%, p<0.01). Following 24h hypertonic (0.3 M) saline exposure, both groups displayed a decrease in 0.15 M NaCl solution intake and preference (days 1+2 after exposure: 10±2% vs 21±4%, p<0.01 vs baseline within each group, and p=0.15 between groups). While control mice maintained this significant suppression of preference for 0.15 M NaCl beyond one week after 24h 0.3 M NaCl exposure (e.g., days 7+8 after exposure: controls 22±3% p=0.01 vs baseline), preference of Arrb2 KO mice for 0.15 M NaCl returned to baseline levels within days (e.g., days 7+8 Arrb2 KO 45±9%, p=0.08 vs baseline, and p<0.01 vs control). This supports the idea that Arrb2 is implicated in Na ingestive behaviors, potentially influencing memory maintenance and retrieval. Future studies aim to characterize the role of Arrb2 downstream of the AT 1 R within specific brain regions in Na consummatory behaviors.

Insights Into the Role of Angiotensin-II AT1 Receptor-Dependent β-Arrestin Signaling in Cardiovascular Disease.

β-arrestins are a family of intracellular signaling proteins that play a key role in regulating the activity of G protein-coupled receptors. The angiotensin-II type 1 receptor is an important G protein-coupled receptor involved in the regulation of cardiovascular function and has been implicated in the progression of cardiovascular diseases. In addition to canonical G protein signaling, G protein-coupled receptors including the angiotensin-II type 1 receptor can signal via β-arrestin. Dysregulation of β-arrestin signaling has been linked to several cardiovascular diseases including hypertension, atherosclerosis, and heart failure. Understanding the role of β-arrestins in these conditions is critical to provide new therapeutic targets for the treatment of cardiovascular disease. In this review, we will discuss the beneficial and maladaptive physiological outcomes of angiotensin-II type 1 receptor-dependent β-arrestin activation in different cardiovascular diseases.

Even periconceptional alcohol consumption can have long-term consequences on heart health in the offspring.

Even periconceptional alcohol consumption can have long-term consequences on heart health in the offspring.

Hypothyroidism and subclinical hypothyroidism and their influence on autonomic cardiovascular regulation and metabolism

The aim of this review is to expose different opinions in the literature on the influence of TH and TSH on the autonomic vegetative regulation of cardiovascular function and metabolism in marked and subclinical hypothyroidism (sHT). Hypothyroidism causes changes in hemodynamics and in lipid metabolism, which are predisposing risk factors for cardiovascular diseases. Subclinical hypothyroidism proceeds asymptomatically but there are changes in the cardiovascular system and its regulation, as well as a possible need for hormonal treatment. Although according to literature sources the social and age groups studied are heterogeneous and different tests have been used to investigate the autonomic vegetative regulation, no single model for investigation and therapeutic behavior, especially in sHT, has yet been established. Heart rate variability (HRV) is determined by the balance of afferent sympathetic and parasympathetic influences on cardiac structures and can be used for risk stratification of cardiovascular complications in patients with hypothyroidism. Early detection of autonomic dysfunction and its treatment may improve the overall prognosis as well as the quality of life of patients with hypothyroidism and sHT and limit the rates of cardiovascular morbidity and mortality in these patients.

Aquaporins in Cardiovascular System.

Recent studies have shown that aquaporins (AQPs) are involved in the regulation of cardiovascular function and the development of related diseases, especially in cerebral ischemia, congestive heart failure, hypertension, and angiogenesis. Therefore, further studies are needed to elucidate the mechanism accounting for the association between AQPs and vascular function-related diseases, which may lead to novel approaches to the prevention and treatment of those diseases. Here we will discuss the expression and physiological roles of AQPs in vascular tissues and summarize recent progress in the research on AQPs related cardiovascular diseases.

Cardiac β-Adrenoceptor Signaling: The New Insight on An Old Target in the Therapy of Cardiovascular Disease

Review Cardiac β-Adrenoceptor Signaling: The New Insight on An Old Target in the Therapy of Cardiovascular Disease Ying Song 1, Anthony Yiu-Ho Woo 2,*, Yan Zhang 3,4,*, and Ruiping Xiao 5,6,7,8 1 Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, 100191, China. 2 School of Life Sciences and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, 110016, China. 3 Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, School of Basic Medical Sciences, Ministry of Education, Peking University Health Science Center, Beijing, 100191, China. 4 Beijing Key Laboratory of Cardiovascular Receptors Research, Peking University, Beijing, 100191, China. 5 State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing, 100871, China. 6 Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China. 7 Beijing City Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing, 100871, China. 8 PKU-Nanjing Joint Institute of Translational Medicine, Nanjing, 210000, China. * Correspondence: yiuhowoo@syphu.edu.cn (Anthony Yiu-Ho Woo), Tel.: +86-24-23986375; zhangyan9876@pku.edu.cn (Yan Zhang), Tel.: +86-10-82805945. Received: 19 October 2022 Accepted: 28 October 2022 Published: 21 December 2022 Abstract: A variety of G protein-coupled receptors (GPCRs) are involved in the regulation of cardiovascular function. The β-adrenoceptors (β-ARs), with three subtypes, are the dominant receptor species in the heart, in which the β1-AR and the β2-AR are considered functional. Stimulation of the β-ARs produces myocardial inotropy via activation of the Gs-cAMP-PKA signaling cascade. Prolonged stimulation of the β1-AR is cardiac harmful because the stimulated β1-AR couples only to Gs proteins and it mediates a cardiotoxic signal. On the other hand, the β2-AR couples dually to both Gs and Gi proteins and the β2-AR-Gi pathway is antiapoptotic. The activated Gi signal also counteracts the β-AR-Gs-promoted positive inotropic effect. Other key players in cardiac β-AR signaling include Ca2+/calmodulin-dependent protein kinases (CaMKs), GPCR kinases (GRKs), β-arrestins and phosphodiesterases. During heart failure, excessive sympathetic stimulation results in the activation of the cardiotoxic β1-AR-CaMKIIδ pathway and the upregulation of GRK2 and Gi in the heart. GRK2 promotes the desensitization of β-ARs and enhances a β2-AR-mediated Gi signaling. These signal transduction processes accompanying the downregulation of the β1-AR are involved in cardiac dysfunction, maladaptive cardiac remodeling, and the progression of chronic heart failure. β-Blockers are widely used in the treatment of cardiovascular disease. They have established their position as one of the “four pillars of heart failure” thirty years ago. In the present review, we provide an overview of the recent progress in the basic research of GPCRs focusing on cardiac β-AR signal transduction.

Interaction of Vitamin D with Peptide Hormones with Emphasis on Parathyroid Hormone, FGF23, and the Renin-Angiotensin-Aldosterone System.

The seminal discoveries that parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) are major endocrine regulators of vitamin D metabolism led to a significant improvement in our understanding of the pivotal roles of peptide hormones and small proteohormones in the crosstalk between different organs, regulating vitamin D metabolism. The interaction of vitamin D, FGF23 and PTH in the kidney is essential for maintaining mineral homeostasis. The proteohormone FGF23 is mainly secreted from osteoblasts and osteoclasts in the bone. FGF23 acts on proximal renal tubules to decrease production of the active form of vitamin D (1,25(OH)2D) by downregulating transcription of 1α-hydroxylase (CYP27B1), and by activating transcription of the key enzyme responsible for vitamin D degradation, 24-hydroxylase (CYP24A1). Conversely, the peptide hormone PTH stimulates 1,25(OH)2D renal production by upregulating the expression of 1α-hydroxylase and downregulating that of 24-hydroxylase. The circulating concentration of 1,25(OH)2D is a positive regulator of FGF23 secretion in the bone, and a negative regulator of PTH secretion from the parathyroid gland, forming feedback loops between kidney and bone, and between kidney and parathyroid gland, respectively. In recent years, it has become clear that vitamin D signaling has important functions beyond mineral metabolism. Observation of seasonal variations in blood pressure and the subsequent identification of vitamin D receptor (VDR) and 1α-hydroxylase in non-renal tissues such as cardiomyocytes, endothelial and smooth muscle cells, suggested that vitamin D may play a role in maintaining cardiovascular health. Indeed, observational studies in humans have found an association between vitamin D deficiency and hypertension, left ventricular hypertrophy and heart failure, and experimental studies provided strong evidence for a role of vitamin D signaling in the regulation of cardiovascular function. One of the proposed mechanisms of action of vitamin D is that it functions as a negative regulator of the renin-angiotensin-aldosterone system (RAAS). This finding established a novel link between vitamin D and RAAS that was unexplored until then. During recent years, major progress has been made towards a more complete understanding of the mechanisms by which FGF23, PTH, and RAAS regulate vitamin D metabolism, especially at the genomic level. However, there are still major gaps in our knowledge that need to be filled by future research. The purpose of this review is to highlight our current understanding of the molecular mechanisms underlying the interaction between vitamin D, FGF23, PTH, and RAAS, and to discuss the role of these mechanisms in physiology and pathophysiology.

Modulation of the miR-122/Sirt-6/ACE2 axis on experimentally-induced myocardial infarction

Myocardial infarction (MI) is a progressive myocardial necrosis that can lead to a number of life-threatening complications. MiRNAs have a crucial role in the pathogenesis of many cardiovascular diseases. Remarkably, miR-122 targets the sirtuin-6 (Sirt-6) gene, which is an essential regulator of cardiovascular function and is considered a partial angiotensin converting enzyme 2 (ACE2) activator. Modulation of this axis is supposed to contribute to MI pathogenesis. The current study aims to investigate the cardioprotective effects of xanthenone through targeting the miR-122/Sirt-6/ACE2 axis on experimentally-induced MI in rats. Xanthenone was administered for 14 days and isoprenaline was injected in the last 2 days of the experiment. Xanthenone treatment resulted in a significant downregulation of miR-122, which further upregulated Sirt-6 and thus activated the adenosine monophosphate-activated protein kinase (AMPK). AMPK increases ACE2 levels and results in a decrease in the level of its substrate angiotensin II resulting in the normalization of the inflammatory cytokines and the cardiac biomarkers. Finally, by targeting the miR-122/Sirt-6/AMPK/ACE2 axis, xanthenone has the potential to be a promising cardioprotective agent against MI.

Sleep Loss Influences the Interconnected Brain-Body Regulation of Cardiovascular Function in Humans.

Poor sleep is associated with hypertension, a major risk factor for cardiovascular disease. However, the mechanism(s) through which sleep loss affects cardiovascular health remains largely unknown, including the brain and body systems that regulate vascular function. Sixty-six healthy adults participated in a repeated-measures, crossover, experimental study involving assessments of cardiovascular function and brain connectivity after a night of sleep and a night of sleep deprivation. First, sleep deprivation significantly increased blood pressure-both systolic and diastolic. Interestingly, this change was independent of any increase in heart rate, inferring a vasculature-specific rather than direct cardiac pathway. Second, sleep loss compromised functional brain connectivity within the vascular control network, specifically the insula, anterior cingulate, amygdala, and ventral and medial prefrontal cortices. Third, sleep loss-related changes in brain connectivity and vascular tone were not independent, but significantly interdependent, with changes within the vascular control brain network predicting the sleep-loss shift toward hypertension. These findings establish an embodied framework in which sleep loss confers increased risk of cardiovascular disease through an impact upon central brain control of vascular tone, rather than a direct impact on accelerated heart rate itself.