In Utero Particulate Matter Exposure Produces Heart Failure, Electrical Remodeling, and Epigenetic Changes at Adulthood

Author:

Tanwar Vineeta12,Gorr Matthew W.12,Velten Markus3,Eichenseer Clayton M.12,Long Victor P.14,Bonilla Ingrid M.1,Shettigar Vikram5,Ziolo Mark T.5,Davis Jonathan P.5,Baine Stephen H.4,Carnes Cynthia A.14,Wold Loren E.152

Affiliation:

1. Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University, Columbus, OH

2. College of Nursing, The Ohio State University, Columbus, OH

3. Department of Anesthesiology and Intensive Care Medicine, Rheinische Friedrich‐Wilhelms‐University, University Medical Center, Bonn, Germany

4. College of Pharmacy, The Ohio State University, Columbus, OH

5. Department of Physiology and Cell Biology, The Ohio State University, Columbus, OH

Abstract

Background Particulate matter (PM; PM 2.5 [PM with diameters of <2.5 μm]) exposure during development is strongly associated with adverse cardiovascular outcomes at adulthood. In the present study, we tested the hypothesis that in utero PM 2.5 exposure alone could alter cardiac structure and function at adulthood. Methods and Results Female FVB mice were exposed either to filtered air or PM 2.5 at an average concentration of 73.61 μg/m 3 for 6 h/day, 7 days/week throughout pregnancy. After birth, animals were analyzed at 12 weeks of age. Echocardiographic (n=9–10 mice/group) and pressure‐volume loop analyses (n=5 mice/group) revealed reduced fractional shortening, increased left ventricular end‐systolic and ‐diastolic diameters, reduced left ventricular posterior wall thickness, end‐systolic elastance, contractile reserve ( dP /dt max /end‐systolic volume), frequency‐dependent acceleration of relaxation), and blunted contractile response to β‐adrenergic stimulation in PM 2.5 ‐exposed mice. Isolated cardiomyocyte (n=4–5 mice/group) function illustrated reduced peak shortening, ± dL / dT , and prolonged action potential duration at 90% repolarization. Histological left ventricular analyses (n=3 mice/group) showed increased collagen deposition in in utero PM 2.5 ‐exposed mice at adulthood. Cardiac interleukin ( IL) ‐6, IL ‐1ß, collagen‐1, matrix metalloproteinase ( MMP ) 9, and MMP 13 gene expressions were increased at birth in in utero PM 2.5 ‐exposed mice (n=4 mice/group). In adult hearts (n=5 mice/group), gene expressions of sirtuin (Sirt) 1 and Sirt2 were decreased, DNA methyltransferase (Dnmt) 1, Dnmt3a, and Dnmt3b were increased, and protein expression (n=6 mice/group) of Ca 2+ ‐ATPase, phosphorylated phospholamban, and Na + /Ca 2+ exchanger were decreased. Conclusions In utero PM 2.5 exposure triggers an acute inflammatory response, chronic matrix remodeling, and alterations in Ca 2+ handling proteins, resulting in global adult cardiac dysfunction. These results also highlight the potential involvement of epigenetics in priming of adult cardiac disease.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Cardiology and Cardiovascular Medicine

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