Atrial natriuretic peptide stimulates autophagy/mitophagy and improves mitochondrial function in chronic heart failure

Abstract

Mitochondrial dysfunction, causing increased reactive oxygen species (ROS) production, is a molecular feature of heart failure (HF). A defective antioxidant response and mitophagic flux were reported in circulating leucocytes of patients with chronic HF and reduced ejection fraction (HFrEF). Atrial natriuretic peptide (ANP) exerts many cardiac beneficial effects, including the ability to protect cardiomyocytes by promoting autophagy. We tested the impact of ANP on autophagy/mitophagy, altered mitochondrial structure and function and increased oxidative stress in HFrEF patients by both ex vivo and in vivo approaches. The ex vivo study included thirteen HFrEF patients whose peripheral blood mononuclear cells (PBMCs) were isolated and treated with αANP (10–11 M) for 4 h. The in vivo study included six HFrEF patients who received sacubitril/valsartan for two months. PBMCs were characterized before and after treatment. Both approaches analyzed mitochondrial structure and functionality. We found that levels of αANP increased upon sacubitril/valsartan, whereas levels of NT-proBNP decreased. Both the ex vivo direct exposure to αANP and the higher αANP level upon in vivo treatment with sacubitril/valsartan caused: (i) improvement of mitochondrial membrane potential; (ii) stimulation of the autophagic process; (iii) significant reduction of mitochondrial mass—index of mitophagy stimulation—and upregulation of mitophagy-related genes; (iv) reduction of mitochondrial damage with increased inner mitochondrial membrane (IMM)/outer mitochondrial membrane (OMM) index and reduced ROS generation. Herein we demonstrate that αANP stimulates both autophagy and mitophagy responses, counteracts mitochondrial dysfunction, and damages ultimately reducing mitochondrial oxidative stress generation in PBMCs from chronic HF patients. These properties were confirmed upon sacubitril/valsartan administration, a pivotal drug in HFrEF treatment.

Mitochondrial Dysfunction in Heart Failure: From Pathophysiological Mechanisms to Therapeutic Opportunities

“…Based on previous evidence that abnormal mitochondrial structure and function are associated with altered mitophagy and increased oxidative stress in HF with reduced ejection fraction (HFrEF) [ 59 ], a recent study tested the impact of ANP (able to stimulate autophagy/mitophagy in cardiomyocytes [ 105 ]) in HFrEF patients by both ex vivo and in vivo approaches [ 106 ]. In the ex vivo study, PBMCs isolated from HFrEF patients were directly exposed to αANP.…”

“…In the ex vivo study, PBMCs isolated from HFrEF patients were directly exposed to αANP. The in vivo study included HFrEF patients who received a treatment with sacubitril/valsartan, a first-line pharmacological therapy consisting in the association of the type 1 angiotensin II receptor and neprilysin inhibitors, the latter causing an increase in NPs, mainly αANP [ 106 ]. Both the ex vivo direct exposure to αANP and the higher αANP level upon in vivo treatment were able to restore mitochondrial membrane potential, to stimulate the autophagic process with an increase in the mitochondrial mass index, to reduce mitochondrial damage with an increased IMM/OMM index, and to decrease ROS levels [ 106 ].…”

“…The in vivo study included HFrEF patients who received a treatment with sacubitril/valsartan, a first-line pharmacological therapy consisting in the association of the type 1 angiotensin II receptor and neprilysin inhibitors, the latter causing an increase in NPs, mainly αANP [ 106 ]. Both the ex vivo direct exposure to αANP and the higher αANP level upon in vivo treatment were able to restore mitochondrial membrane potential, to stimulate the autophagic process with an increase in the mitochondrial mass index, to reduce mitochondrial damage with an increased IMM/OMM index, and to decrease ROS levels [ 106 ]. According to these results, the favorable effects of NPs on mitochondrial function may contribute to explain, at least in part, the efficacy of sacubitril/valsartan in reducing cardiovascular mortality and HF hospitalizations and their role as a first-line strategy in the therapeutic management of HF.…”

Hypertension and Heart Failure: From Pathophysiology to Treatment

“…Oxidative damage contributes to impairment of the electron transport chain, to mitochondrial uncoupling, and finally to bioenergetic dysfunction, which promotes cell death. [ 38 , 39 ]. In addition, shear stress due to hypertension is associated with the activation of different biological pathways, such as PKC epsilon, c-Jun N-terminal kinase (JNK), MAP kinase, and p53, contributing to atherosclerotic plaque progression and a further worsening of endothelial function [ 40 , 41 , 42 ], contributing to the progression to HFrEF ( Figure 1 ).…”

Natriuretic Peptide Signaling in Uterine Biology and Preeclampsia

“…The ANP signaling mechanism in trophoblasts is not fully understood. In the heart, ANP modulates autophagy, a process of regulating cellular function depending on pathophysiological conditions [135,136]. In a recent study in human trophoblasts and chorionic villi, a molecular mechanism has been suggested, in which ANP activates NPR-A and subsequent adenosine 5 -monophosphate-activated protein kinase (AMPK) and the mammalian target of rapamycin complex 1 (mTORC1) signaling to inhibit autophagy and induce protein kinase N3 (PKN3) expression, thereby increasing metalloproteinase expression and trophoblast invasiveness [134] (Figure 4).…”