bims-hafaim 2025-10-05 papers

Issue of 2025–10–05
five papers selected by
Kyle McCommis, Saint Louis University

Am J Physiol Endocrinol Metab. 2025 Oct 03.

Diabetic heart shows preferential secretion of inner mitochondrial membrane proteins in the presence of mitochondrial oxidative stress.

Paula M Miotto, Jacqueline Bayliss, Gio Fidelito, James R Bell, Lea M D Delbridge, Matthew J Watt, Magdalene K Montgomery.

Heart disease, including diabetic cardiomyopathy, is a leading cause of mortality in patients with type 2 diabetes (T2D). Defects in heart function are accompanied by marked changes in cardiac metabolism, including dysregulation of lipid and glucose metabolism, mitochondrial dysfunction, and oxidative stress. In addition to these metabolic defects, the heart is an important endocrine organ. However, while T2D has been shown to impact the secretome of liver, skeletal muscle and adipose tissue (among others), little is known about the secretome of the heart, and the influence of T2D on cardiac protein secretion. Using precision-cut heart slices from mice with insulin resistance (20-weeks of high-fat feeding) and T2D (db/db mice) compared to their respective controls, we performed mass spectrometry proteomics analysis of cardiac protein secretion as well as proteins contained within extracellular vesicles (EV). We reveal striking remodelling of cardiac protein secretion in T2D but not diet-induced insulin resistance. Specifically, we show a marked increase in the secretion of inner mitochondrial membrane (IMM) proteins in T2D, which was accompanied by a disproportional accumulation of outer mitochondrial membrane proteins within the heart. This was associated with increased mitochondrial oxidative stress, selective oxidative damage to IMM proteins, and reduced markers of LC3-mediated mitophagy in the db/db heart, highlighting secretion of mitochondrial components as a potential alternative pathway for mitochondrial quality control. Altogether, this study provides an in-depth proteomics analysis showing remodelling of cardiac protein secretion in T2D and provides insights into a possible link between mitochondrial oxidative stress and the release of mitochondrial components.

Keywords: cardiokine; diabetic heart; endocrine; mitochondrial dysfunction; oxidative stress

DOI: https://doi.org/10.1152/ajpendo.00073.2025

Front Pharmacol. 2025 ;16 1600410

Improved myocardial mitochondrial energy metabolism in rats with chronic heart failure by modifying fatty acid oxidation using an extract of sand-fired aconite (Jianchang gang processing).

Hongtao Zhang, Yi Huang, Songhong Yang, Feipeng Gong, Yuncheng Gu, Qin Xie, Yanrong Ye, Xingmei Lu, Lingyun Zhong.

Introduction: Sand-fired aconite slices (SFAS) demonstrate anti-heart failure effects, but the mechanism remains unclear. This study investigated myocardial mitochondrial energy metabolism as a therapeutic mechanism of SFAS in doxorubicin-induced chronic heart failure (CHF) rats.
Methods: The CHF rat model was established via the intraperitoneal injection of doxorubicin (DOX). Following successful model production, rats were randomly assigned to nine groups. After drug administration, their cardiac function was assessed, and their cardiac tissue morphology and myocardial mitochondria were examined. Atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), norepinephrine (NE), malondialdehyde (MDA), superoxide dismutase (SOD), free fatty acid (FFA), sodium-potassium-ATPase (Na+-k+-ATPase), calcium-magnesium-ATPase (Ca2+-Mg2+-ATPase), and adenosine triphosphate (ATP) levels were quantified using enzyme-linked immunosorbent assays (ELISAs). Fatty acid translocase (CD36), carnitine palmitoyl transferase 1 (CPT1), adenosine 5'-monophosphate-activated protein kinase (AMPK), phosphorylated adenosine monophosphate-activated protein kinase (p-AMPK), peroxisome proliferator-activated receptor γ coactivator 1 alpha (PGC-1α), and Sirtuin 3 (SIRT3) protein expression levels were assessed by Western blot.
Results: SFAS significantly improved cardiac function in CHF rats. It increased the left ventricular ejection fraction (LVEF) (from 34.22% ± 2.03%-83.68% ± 2.34%; P < 0.001) and left ventricular shortening fraction (LVFS) (from 17.06% ± 1.08%-53.86% ± 2.82%; P < 0.001) and decreased ANP (from 551.29 ± 14.63 pg/mL to 291.96 ± 11.28 pg/mL; P < 0.05), BNP (from 743.15 ± 18.03 pg/mL to 478.75 ± 10.57 pg/mL; P < 0.001), and NE levels (from 1,105.36 ± 21.79 pg/mL to 672.67 ± 6.70 pg/mL; P < 0.001). Additionally, it decreased MDA production (from 8.89 ± 0.36 nmol/mL to 5.11 ± 0.35 nmol/mL; P < 0.05) and increased SOD activity (from 264.82 ± 4.26 pg/mL to 529.64 ± 10.27 pg/mL; P < 0.001), Na+-K+-ATPase levels (from 7.19 ± 0.65 μmol/mL to 14.08 ± 0.28 μmol/mL; P < 0.001), Ca2+-Mg2+-ATPase levels (from 0.86 ± 0.03 μmol/mL to 1.40 ± 0.02 μmol/mL; P < 0.05), CD36 levels (P < 0.05), and CPT1 levels (P < 0.01). Moreover, it improved mitochondrial structural damage and reduced the level of oxidative stress in cardiomyocytes. Furthermore, SFAS promoted FFA oxidation (from 1,477.49 ± 7.60 μmol/mL to 768.87 ± 82.53 μmol/mL; P < 0.05) and ATP production (from 2,869.85 ± 298.26 nmol/mL to 5,483.17 ± 120.03 nmol/mL; P < 0.001) and increased p-AMPK, PGC-1α, and SIRT3 levels (P < 0.05 and P < 0.01).
Conclusion: By activating the AMPK/PGC-1α/SIRT3 signaling pathway, SFAS ameliorated the impaired fatty acid oxidation pathway and enhanced mitochondrial function and antioxidant capacity in cardiomyocytes, ultimately reducing myocardial damage and restoring cardiac function in CHF rats.

Keywords: chronic heart failure; energy metabolism; fatty acid; mitochondria; oxidative stress; sand fired aconite slices

DOI: https://doi.org/10.3389/fphar.2025.1600410

JACC Heart Fail. 2025 Sep 30. pii: S2213-1779(25)00514-1. [Epub ahead of print]13(11): 102586

Congestion and Low Cardiac Output Hemodynamic Phenotype Drives Outcomes in Overweight and Obese HFpEF.

Vivek P Jani, Joban Vaishnav, Soumya Vungarala, Virginia S Hahn, Danielle Hopkins, Rishi Trivedi, Wendy Ying, David A Kass, Dhananjay Vaidya, Kavita Sharma.

BACKGROUND: Hemodynamic assessment of congestion and perfusion in overweight and obese patients with heart failure with preserved ejection fraction (HFpEF), and the respective impact of hemodynamic phenotypes on clinical outcomes has been limited to date.
OBJECTIVES: The authors characterized predominantly overweight and obese HFpEF patients by hemodynamic assessment of congestion and perfusion status and correlated these hemodynamic phenotypes with clinical outcomes.
METHODS: A total of 227 patients referred to the Johns Hopkins HFpEF Clinic meeting clinical criteria for HFpEF and with right heart catheterization assessment were included. Hemodynamic-based groups were assigned as follows: dry-warm (pulmonary capillary wedge pressure [PCWP] <15 mm Hg, cardiac index >2.2 L/min/m2), wet-warm (PCWP ≥15 mm Hg, cardiac index >2.2 L/min/m2), dry-cold (PCWP <15 mm Hg, cardiac index ≤2.2 L/min/m2), and wet-cold (PCWP ≥15 mm Hg, cardiac index ≤2.2 L/min/m2).
RESULTS: Compared to "warm" profile patients, HFpEF subjects classified as "cold" profile (dry-cold + wet-cold) accounted for 34% of the cohort and were more likely to be older (cold: 68 ± 11 years vs warm: 62 ± 12 years; P = 0.002), male (cold: 51% vs warm 66%; P = 0.04), have atrial fibrillation (P = 0.0007), with higher N-terminal pro-B-type natriuretic peptide (P = 0.03), and higher pulmonary vascular resistance indices. Of the 4 hemodynamic groups, wet-cold patients had the highest N-terminal pro-B-type natriuretic peptide levels (469 pg/mL [Q1-Q3: 257-1,389 pg/mL]; overall P = 0.0001), highest rate of atrial fibrillation (54%, overall P = 0.001), and were more likely to be on beta-blocker therapy (68%; P = 0.05). Kaplan-Meier survival analysis (median follow-up time: 39 months) revealed that HFpEF patients with low cardiac perfusion (thermodilution method and Fick method) had worse mortality even after accounting for potential overcorrection from body mass index.
CONCLUSIONS: In a predominantly overweight and obese HFpEF cohort meeting standard diagnostic criteria for clinical HFpEF, 34% had a depressed cardiac index on hemodynamic testing. Hemodynamic assessment may identify an under-recognized low-output hemodynamic phenotype in HFpEF, which in combination with congestion, is associated with worse clinical outcomes.

Keywords: heart failure with preserved ejection fraction; hemodynamics; metabolic syndrome; obesity

DOI: https://doi.org/10.1016/j.jchf.2025.102586

Physiol Rep. 2025 Oct;13(19): e70586

Multiomics investigation of the female hypertensive human heart.

Hypertension affects 1 in 2 adults in the United States and is the leading risk factor for myocardial infarction and chronic kidney disease. While animal models have advanced our understanding of the effects of hypertension on the heart, molecular insight from human cardiovascular tissues is currently lacking. Building upon previous work describing a protocol for the systematic dissection and preservation of whole postmortem human hearts, we performed pilot multiomics analyses of postmortem human hearts from donors with (n = 3) and without (n = 2) hypertension. Using bulk RNA-seq, we identified a higher abundance of transcripts associated with DNA helicase activity, NAD-dependent deacetylase activity, and branched chain amino acid metabolism in hypertension compared to normotension. Using single-nucleus RNA-seq, we identified a loss of contractile vascular smooth muscle cells and greater endothelial cell proliferation associated with hypertension. Lastly, metabolomics revealed an abundance of metabolites upstream of NAD-dependent metabolic steps in fatty acid oxidation and the Krebs cycle, consistent with reductive stress, and a likely funneling of glycolytic intermediates into the pentose phosphate pathway. Together, these methods demonstrate a powerful technique for the investigation of human cardiovascular disease and lend insight into the molecular signature of hypertension in adult cardiac tissue.

Keywords: biobanking; cardiac metabolism; hypertension; multiomics

DOI: https://doi.org/10.14814/phy2.70586

J Lipid Res. 2025 Oct 01. pii: S0022-2275(25)00182-8. [Epub ahead of print] 100920

Cardiac lipid droplets differ under pathological and physiological conditions.

Ni-Huiping Son, Sunny Son, Michael Verano, Zhen-Xiu Liu, Waqas Younis, Makenzie Komack, Kelly V Ruggles, Jana Gjini, Song-Tao Tang, Ainara Gonzalez Cabodevilla, Feng-Xia Liang, Hai-Zhen Wang, Dimitrios Nasias, José O Alemán, Ira J Goldberg.

Excessive accumulation of lipids within cardiomyocytes can sometimes initiate cardiomyopathy, while in other situations excess lipids do not cause harm. To understand how pathologic and non-pathologic lipid accumulation differ, we isolated lipid droplets (LDs) from two genetically altered mouse lines and from wild-type (WT) mice after an overnight fast. The LDs from MHC-peroxisomal proliferator-activated receptor γ1(MHC-Pparg1) transgenic mice were 3-fold larger than those from either fasted WT or non-cardiomyopathy MHC-diacylglycerol acyl transferase 1 (MHC-Dgat1) transgenic mice. Proteomic analysis of the LD associated membrane proteins (LDAMPs) showed that MHC-Pparg1 LDs had less perilipin (Plin). Proteins associated with lipolysis and LD formation (CIDEs and MTP), lipid synthesis, and Pparg signaling pathways were increased in MHC-Pparg1 LDAMPs. Unlike in MHC-Pparg1, MHC-Dgat1 LDAMPs exhibited increased mitochondrial peroxidative proteins with reduced adipose triglyceride lipase (Pnpla2), and Pparg coactivator 1 alpha (Pgc1A). Cardiomyocytes from MHC-Pparg1 hearts had transmission electron microscopy (TEM) images of ongoing lipolysis and greater amounts of lipolytic proteins. In contrast, images from MHC-Dgat1 cardiomyocytes showed more lipophagy. Consistent with the proteomic study and EM images, cardiac immunofluorescence staining showed that Plin 5 protein, thought to block LD lipolysis, was markedly reduced with MHC-Pparg1 overexpression, while hormone sensitive lipase was increased. The autophagosome marker protein LC3B was increased in MHC-Dgat1 but not in MHC-Pparg1 hearts. Potentially toxic lipids like diacylglycerols and ceramides were increased in hearts but not LDs from MHC-Pparg1 mice. Our data indicates that cardiomyocyte LDs vary in size, composition, and metabolism. Cardiotoxicity was associated with greater LD lipolysis, which we postulate leads to intracellular release of toxic lipids.

Keywords: ceramides; heart failure; lipidomics; lipolysis; lipotoxicity; proteomics

DOI: https://doi.org/10.1016/j.jlr.2025.100920