Cholinergic Elicitation Prevents Ventricular Remodeling via Alleviations of Myocardial Mitochondrial Injury Linked to Inflammation in Ischemia-Induced Chronic Heart Failure Rats

Abstract

Background. Cholinergic anti-inflammatory pathway (CAP) is implicated in cardioprotection in chronic heart failure (CHF) by downregulating inflammation response. Mitochondrial injuries play an important role in ventricular remodeling of the CHF process. Herein, we aim to investigate whether CAP elicitation prevents ventricular remodeling in CHF by protecting myocardial mitochondrial injuries and its underlying mechanisms. Methods and Results. CHF models were established by ligation of anterior descending artery for 5 weeks. Postoperative survival rats were assigned into 5 groups: the sham group (sham, n = 10 ), CHF group (CHF, n = 11 ), Vag group (CHF+vagotomy, n = 10 ), PNU group (CHF+PNU-282987 for 4 weeks, n = 11 ), and Vag+PNU group (CHF+vagotomy+PNU-282987 for 4 weeks, n = 10 ). The antiventricular remodeling effect of cholinergic elicitation was evaluated in vivo, and H9C2 cells were selected for the TNF-α gradient stimulation experiment in vitro. In vivo, CAP agitated by PNU-282987 alleviated the left ventricular dysfunction and inhibited the energy metabolism remodeling. Further, cholinergic elicitation increased myocardium ATP levels and reduced systemic inflammation. CAP induction alleviates macrophage infiltration and cardiac fibrosis, of which the effect is counteracted by vagotomy. Myocardial mitochondrial injuries were ameliorated by CAP activation, including the reserved ultrastructural integrity, declining ROS overload, reduced myocardial apoptosis, and enhanced mitochondrial fusion. In vitro, TNF-α intervention significantly exacerbated the mitochondrial damage in H9C2 cells. Conclusion. CAP elicitation effectively improves ischemic ventricular remodeling by suppressing systemic and cardiac inflammatory response, attenuating cardiac fibrosis and potentially alleviating the mitochondrial dysfunction linked to hyperinflammation reaction.

Cooling Down Inflammation in the Cardiovascular System via the Nicotinic Acetylcholine Receptor

“…This in turn results in the activation of a series of downstream events such as apoptosis and hyperinflammation. 152,153 In a rat model of chronic HF induced by ischemia, PNU-282987 treatment ameliorated mitochondrial injury and decreased ROS overload (Fig. 4).…”

“…4). 153 Consequently, mitochondria-mediated cardiomyocyte apoptosis was alleviated. ROS can cause cell death by acting as an upstream activator of excessive autophagy, which is essential for maintaining cellular homeostasis and normal cell function at the basal level.…”

Protective Effects of Resveratrol on Adolescent Social Isolation-Induced Anxiety-Like Behaviors via Modulating Nucleus Accumbens Spine Plasticity and Mitochondrial Function in Female Rats

“…A Cytochrome-c oxidase activity assay kit was used to measure the activity of cytochrome C oxidase in the NAc and expressed as U/mg protein [ 37 ]. The NAc adenosine triphosphate (ATP) content was assessed using an ATP Assay Kit according to the manufacturer’s instructions [ 38 ].…”

Pretreatment of kaempferol-3-O-rutinoside protects H9c2 cells against LPS-induced inflammation through the AMPK/SIRT1 pathway

“…Chronic heart failure (CHF) is a common cardiovascular disease and a serious end-stage of various heart diseases, which seriously threatens the health of patients (D' Alessandra et al, 2020). Ventricular remodeling (VR) after acute myocardial infarction (AMI) is the pathophysiological basis for the development of CHF (Zhao et al, 2021). The myocardium in the infarcted area becomes thinner and dilated, while the myocardium in the non-infarcted area becomes hypertrophic and elongated, leading to the enlargement and deformation of the ventricular cavity, resulting in decrease of ventricular systolic function (Schumacher et al, 2019).…”