Circulation research最新文献

Background: CPT1 (carnitine palmitoyltransferase 1) is a rate-limiting enzyme for long-chain fatty acid oxidation. In adult hearts, CPT1b predominates, while CPT1a is coexpressed at lower levels. Pathological stress on the heart induces CPT1a expression, coinciding with a reduction in fatty acid oxidation, yet the role of CPT1a in pathological remodeling is unknown.

Methods: CPT1 isoform expression was assayed in the myocardium of patients with heart failure with nonischemic cardiomyopathy and a preclinical mouse model of heart failure. Mice were subjected to afterload stress via transverse aortic constriction (TAC) or sham surgery (sham) with cardiac-specific CPT1a knockdown or cardiac-specific, adeno-associated virus serotype 9 (AAV9)-mediated CPT1a overexpression (AAV9.cTnT [cardiac troponin T].Cpt1a) versus empty virus or PBS infusions as controls. MicroRNA 370, known to suppress hepatic CPT1a, was assayed and overexpressed to determine if microRNA 370 regulates cardiac CPT1a expression.

Results: CPT1a protein was elevated and microRNA 370 reduced in the myocardium of male and female patients with nonischemic cardiomyopathy, as well as in failing mouse hearts. AAV9-mediated microRNA 370 overexpression in mouse hearts suppressed CPT1a expression and attenuated the response of CPT1a to TAC. Preventing CPT1a upregulation in response to TAC in cardiac-specific CPT1a knockout mice exacerbated adverse remodeling, severe dysfunction, and increased mortality. In contrast, CPT1a overexpression (2.8-fold) attenuated impaired ejection fraction (by 54%) versus control TAC hearts (P<0.05). Delivery of AAV9.cTnT.Cpt1a 4 weeks after TAC surgery led to significant rescue of ejection fraction and mitigated the exacerbated dysfunction of cardiac-specific CPT1a knockout mice TAC hearts. RNA-seq revealed a novel function of CPT1a in suppressing hypertrophic, profibrotic, and cell death gene programs in both sham and TAC hearts, irrespective of changes in fatty acid oxidation, with reduced histone acetylation.

Conclusions: The effects of CPT1a in the heart extend beyond fatty acid oxidation including noncanonical regulation of gene programs. CPT1a upregulation occurs in nonischemic cardiomyopathy and is a critical cardioprotective adaptation to pathological stress.

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.