Circulation research最新文献

Background: Short-term blood pressure (BP) variability is increasingly recognized as an independent predictor of cardiovascular and cerebrovascular risks, yet the central neural mechanisms that govern this variability, particularly across behavioral states, remain poorly defined.

Methods: We investigated the role of rostral ventrolateral medulla C1 (RVLM^C1) neurons in short-term BP regulation during sleep-wake transitions and physical activity in freely behaving rats. Genetically targeted fiber photometry was used to record RVLM^C1 neuronal activity across behavioral states. The contribution of feedback from the arterial baroreflex to the activity of RVLM^C1 neurons was assessed using sinoaortic denervation. Selective genetic ablation of RVLM^C1 neurons was performed to determine their role in BP regulation.

Results: RVLM^C1 neurons exhibited state-dependent activity, with rapid activation during arousal from nonrapid eye movement sleep, sustained activity during rapid eye movement sleep, and further recruitment during physical activity. Baroreflex input contributed to the modulation of RVLM^C1 neuron activity by pharmacological manipulations of BP and transitions from nonrapid eye movement sleep to rapid eye movement sleep. Selective ablation of RVLM^C1 neurons did not alter mean BP but resulted in marked BP instability during arousal and movement.

Conclusions: RVLM^C1 neurons stabilize BP during changes in the behavioral state by integrating arousal-related central drive with baroreceptor feedback. Disruption of these neurons leads to increased short-term BP variability despite preserved mean BP, providing a potential neural mechanism underlying pathological BP instability.

Background: Atherosclerosis commences with endothelial dysfunction and the retention of cholesterol within the vessel wall, followed by a chronic inflammatory response. Lowering LDL-C (low-density lipoprotein-cholesterol; such as statins and PCSK9 [proprotein convertase subtilisin/kexin type 9] inhibitors) is the mainstay of current treatment for patients with atherosclerotic cardiovascular diseases, but residual inflammatory risk remains high.

Methods: To address this pressing challenge, we used connectivity map screening of Food and Drug Administration-approved drugs, using perturbational data sets obtained from TNF-α (tumor necrosis factor-α) and IL (interleukin)-1β-stimulated human endothelial cells. Male and female Ldlr^-/- mouse models were used to evaluate the in vivo antiatherosclerotic effect of the hit compound identified.

Results: This screening endeavor allows us to identify neratinib, a clinical drug against breast cancer, as the hit compound with broad anti-inflammatory actions in endothelial cells. Further studies reveal that neratinib inhibited endothelial cell inflammation elicited by 3 different proinflammatory stimuli (TNF-α, IL-1β, and lipopolysaccharide). Intriguingly, the anti-inflammatory effect of neratinib was independent of its classical target HER2 (human epidermal growth factor receptor 2)/ERBB2 inhibition. Further mechanistic investigation revealed that neratinib directly binds to ASK1 (apoptosis signal-regulating kinase 1) and suppresses ASK1 activation. Importantly, in both male and female Ldlr^-/- mice, treatment with neratinib decreased the plaque burden, reduced the necrotic core size, and mitigated lesional macrophage infiltration. Of translational impact, we observed that neratinib, in conjunction with the use of rosuvastatin (a standard lipid-lowering drug), produced superior antiatherosclerotic effects compared with statin monotherapy. Olink proteomics study pinpointed that combination treatment alleviated inflammation-related cytokines/chemokines in the serum from Ldlr^-/- mice.

Conclusions: Taken together, these findings support the concept that neratinib could be tested as a repurposed drug for vascular inflammation and atherosclerosis, thereby streamlining efforts to translate preclinical discoveries to clinical testing in humans.

Cardiovascular diseases represent a leading cause of mortality across the world. Despite success in managing cardiovascular risk factors, ischemic heart disease, and chronic heart failure, there remains ample opportunity to identify additional mechanisms of disease and therapeutic approaches. Growing insights into the temporal-spatial dynamics of immune responses across cardiovascular diseases have fueled the emergence of cardioimmunology as a promising field for interdisciplinary and translational research. The advent of high-throughput, single-cell multiomics has allowed for unprecedented advances in our understanding of cardiovascular immunology, among major causes of mortality, including myocardial infarction and ischemic heart disease, abdominal aortic aneurysm, and congenital heart disease. In this review, we will highlight specific immune cells and targetable effector mechanisms by which they influence cardiovascular disorders with a focus on congenital heart diseases, myocardial infarction, and abdominal aortic aneurysm.

Almost 200 years of histological and molecular analysis has established that functional shifts in vascular cell populations are associated with healthy vascular function and the progression of vascular disease. Now, new methods in single-cell analysis are serving to dramatically accelerate the study of vascular cell heterogeneity. Here, we will outline the experimental and computational technologies that have made high-throughput analysis of single cells possible, and review recent studies applying these approaches to vascular cells and tissues. In particular, the application of single-cell or single-nucleus RNA sequencing has identified rare and disease-specific cell populations, drivers of cellular heterogeneity, and specific vascular disease-relevant cell populations. High-throughput approaches linking CRISPR (clustered regularly interspaced short palindromic repeats) perturbations to single-cell RNA sequencing data are providing new insights into cell type-specific mechanisms of disease, and connecting human genetic data to these mechanisms. Other single-cell approaches are providing insights into regulatory mechanisms by linking chromatin accessibility to transcription in single cells and revealing the spatial positioning of rare cell types in vascular tissues. With a variety of well-established methods and the continued development of new technologies, single-cell approaches are becoming indispensable and powerful avenues for discovering and detailing new mechanisms of vascular disease.