β1 adrenoceptor antibodies induce myocardial apoptosis via inhibiting PGC-1α-related pathway

Abstract

Background: Peripartum cardiomyopathy (PPCM) is life-threatening heart disease. However, the causes and pathogenesis of PPCM remain unclear. Previous studies found that β1 adrenoceptor antibodies (β1AA) had possible involvement in the development of PPCM. In the present study, we determined the potential relationship between PPCM and β1AA, including the mechanism of β1AA leading to PPCM. Methods: We extracted the β1AA from the postpartum Wistar rats that were injected by the antigen peptide segment of the β1 adrenoceptor to produce PPCM. We tested the effects of β1AA on H9C2 cell line by CCK-8, LDH, TUNEL, SA-ELISA, qRT-PCR, and western blot methods. Furthermore, PGC-1α was overexpressed to rescue the effect of β1AA on H9C2 cells. Results: We found that the extracted β1AA induced apoptosis of cardiac myocytes of H9C2 cell line. Moreover, the expression of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), which is a master regulator of mitochondrial metabolism, and its downstream transcript vascular endothelial growth factor (VEGF) got decreased in H9C2 cells after β1AA treatment. In addition, the effect of β1AA could be inhibited by atenolol, the antagonist of β1 adrenoceptors (β1AR) and imitated by isoprenaline, the agonist of β1AR. Furthermore, overexpression of PGC-1α in the H9C2 cells rescued the apoptosis of cells and inhibitory expression of VEGF induced by β1AA. Conclusions: Our results suggest that the symptoms of PPCM due to myocardial cell apoptosis induced by β1AA inhibiting the PGC-1α-related pathway impairs mitochondrial energy metabolism. Therefore, our results uncover a previously unknown role of the β1AA pathway in the etiology of PPCM and provide a novel potential target for the treatment of PPCM.

Atractylenolide III Attenuates Apoptosis in H9c2 Cells by Inhibiting Endoplasmic Reticulum Stress through the GRP78/PERK/CHOP Signaling Pathway

“…CHOP downregulates expression of Bcl-2 and increases the translocation of Bax from the cytoplasm to mitochondria, inducing the release of Cyt-c by mitochondria to activate Caspase-3 and induce apoptosis [ 43 ]. Apoptosis is important in the development of HF, which is essential to the pathological process of HF [ 44 ]. In this study, ATL-III could reduce the levels of phosphorylation-PERK, phosphorylation-eIF2 α , and ATF4.…”

Targeting Adrenergic Receptors in Metabolic Therapies for Heart Failure

“…Similarly, β 1 -AR autoantibodies induce a positive inotropy in the heart [ 385 ] but also induce HF [ 386 , 387 ], apoptosis [ 388 ] and inhibit the PPAR pathway [ 389 , 390 ]. However, the metabolic protective effects of a β 2 -AR agonist, higenamine, against mitochondrial and respiratory dysfunction is mediated though increased PPARα signals [ 391 ] ( Figure 2 ). These results suggest that β 1 -AR selective blockers may be better at increasing mitochondrial function during HF than non-selective β-blockers.…”

ENZYME-LINKED IMMUNOSORBENT ASSAY OF AUTOANTIBODIES AGAINST HUMAN Β1-Adrenergic RECEPTOR USING RECOMBINANT ANTIGENS

“…В настоящее время накопилась обширная научная информация по действию аутоиммунных процессов при разных заболеваниях, в том числе сердечно-сосудистых, таких как, например, дилатационная кардиомиопатия (ДКМП) [1][2][3][4][5]. У части пациентов с таким диагнозом обнаруживают аутоантитела к β 1 -адренорецептору [7][8][9][10].…”