Immune profiling of murine cardiac leukocytes identifies triggering receptor expressed on myeloid cells 2 as a novel mediator of hypertensive heart failure

Author:

Smart Charles Duncan1,Fehrenbach Daniel J2,Wassenaar Jean W3,Agrawal Vineet3,Fortune Niki L4,Dixon Debra D3,Cottam Matthew A1,Hasty Alyssa H14,Hemnes Anna R5,Doran Amanda C36,Gupta Deepak K37ORCID,Madhur Meena S1236ORCID

Affiliation:

1. Department of Molecular Physiology and Biophysics, Vanderbilt University , 2201 West End Ave, Nashville, TN 37235 , USA

2. Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center (VUMC) , 2215 Garland Avenue, P415D MRB IV, Nashville, TN 37232 , USA

3. Department of Medicine, Division of Cardiovascular Medicine, Vanderbilt University Medical Center (VUMC) , 1311 Medical Center Dr, Nashville, TN 37232 , USA

4. VA Tennessee Valley Healthcare System , Nashville, TN 37212 , USA

5. Department of Medicine, Division of Allergy, Pulmonary and Critical Care, Vanderbilt University Medical Center (VUMC) , Nashville, TN , USA

6. Vanderbilt Institute for Infection, Immunology, and Inflammation , Vanderbilt University Medical Center (VUMC), Medical Center North A-5121, 1161 21st Ave South, Nashville, TN 37232 , USA

7. Vanderbilt Translational and Clinical Cardiovascular Research Center, Vanderbilt University Medical Center , Nashville, TN , USA

Abstract

Abstract Aims Heart failure with preserved ejection fraction (HFpEF) is characterized by diastolic dysfunction, microvascular dysfunction, and myocardial fibrosis with recent evidence implicating the immune system in orchestrating cardiac remodelling. Methods and results Here, we show the mouse model of deoxycorticosterone acetate (DOCA)-salt hypertension induces key elements of HFpEF, including diastolic dysfunction, exercise intolerance, and pulmonary congestion in the setting of preserved ejection fraction. A modified single-cell sequencing approach, cellular indexing of transcriptomes and epitopes by sequencing, of cardiac immune cells reveals an altered abundance and transcriptional signature in multiple cell types, most notably cardiac macrophages. The DOCA-salt model results in differential expression of several known and novel genes in cardiac macrophages, including up-regulation of Trem2, which has been recently implicated in obesity and atherosclerosis. The role of Trem2 in hypertensive heart failure, however, is unknown. We found that mice with genetic deletion of Trem2 exhibit increased cardiac hypertrophy, diastolic dysfunction, renal injury, and decreased cardiac capillary density after DOCA-salt treatment compared to wild-type controls. Moreover, Trem2-deficient macrophages have impaired expression of pro-angiogenic gene programmes and increased expression of pro-inflammatory cytokines. Furthermore, we found that plasma levels of soluble TREM2 are elevated in DOCA-salt treated mice and humans with heart failure. Conclusions Together, our data provide an atlas of immunological alterations that can lead to improved diagnostic and therapeutic strategies for HFpEF. We provide our dataset in an easy to explore and freely accessible web application making it a useful resource for the community. Finally, our results suggest a novel cardioprotective role for Trem2 in hypertensive heart failure.

Funder

National Institutes of Health

American Heart Association

Publisher

Oxford University Press (OUP)

Subject

Physiology (medical),Cardiology and Cardiovascular Medicine,Physiology

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