Format

Send to

Choose Destination
Arterioscler Thromb Vasc Biol. 2015 Jun;35(6):1401-12. doi: 10.1161/ATVBAHA.115.305566. Epub 2015 Apr 16.

Cardiomyopathy and Worsened Ischemic Heart Failure in SM22-α Cre-Mediated Neuropilin-1 Null Mice: Dysregulation of PGC1α and Mitochondrial Homeostasis.

Author information

1
From the Department of Biochemistry and Molecular Biology (Y.W., Y.C., S.B., A.K.S., E.W., L.H.H., S.K.D., E.B.L., D.M.), Center for Regenerative Medicine, Marriott Heart Disease Research Program, Division of Cardiovascular Diseases, Departments of Medicine, Molecular Pharmacology and Experimental Therapeutics, and Medical Genetics (S.Y., A.T.), Department of Anesthesiology (V.N., J.C.-P., E.N.C.), Department of Health Sciences Research, Division of Biomedical Statistics and Informatics, Health Science Program (K.S., J.-P.A.K.), Department of Gastroenterology (V.S.), and Thoracic Diseases Research Unit, Department of Biochemistry and Molecular Biology (E.B.L.), Mayo Clinic, Rochester, MN; Molecular Cardiology and Angiogenesis Laboratory, Department of Surgery (M.T., M.J., M.T.R., J.A.S., N.M.) and Department of Cell Biology, Center for Vascular Biology (K.P.C.), University of Connecticut Health Center, Farmington; Department of Surgery, Saint Mary's Hospital, Waterbury, CT (M.J., M.T.R., J.A.S.); and Yale Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT (M.S.).
2
From the Department of Biochemistry and Molecular Biology (Y.W., Y.C., S.B., A.K.S., E.W., L.H.H., S.K.D., E.B.L., D.M.), Center for Regenerative Medicine, Marriott Heart Disease Research Program, Division of Cardiovascular Diseases, Departments of Medicine, Molecular Pharmacology and Experimental Therapeutics, and Medical Genetics (S.Y., A.T.), Department of Anesthesiology (V.N., J.C.-P., E.N.C.), Department of Health Sciences Research, Division of Biomedical Statistics and Informatics, Health Science Program (K.S., J.-P.A.K.), Department of Gastroenterology (V.S.), and Thoracic Diseases Research Unit, Department of Biochemistry and Molecular Biology (E.B.L.), Mayo Clinic, Rochester, MN; Molecular Cardiology and Angiogenesis Laboratory, Department of Surgery (M.T., M.J., M.T.R., J.A.S., N.M.) and Department of Cell Biology, Center for Vascular Biology (K.P.C.), University of Connecticut Health Center, Farmington; Department of Surgery, Saint Mary's Hospital, Waterbury, CT (M.J., M.T.R., J.A.S.); and Yale Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT (M.S.). mukhopadhyay.debabrata@mayo.edu.

Abstract

OBJECTIVE:

Neuropilin-1 (NRP-1) is a multidomain membrane receptor involved in angiogenesis and development of neuronal circuits, however, the role of NRP-1 in cardiovascular pathophysiology remains elusive.

APPROACH AND RESULTS:

In this study, we first observed that deletion of NRP-1 induced peroxisome proliferator-activated receptor γ coactivator 1α in cardiomyocytes and vascular smooth muscle cells, which was accompanied by dysregulated cardiac mitochondrial accumulation and induction of cardiac hypertrophy- and stress-related markers. To investigate the role of NRP-1 in vivo, we generated mice lacking Nrp-1 in cardiomyocytes and vascular smooth muscle cells (SM22-α-Nrp-1 KO), which exhibited decreased survival rates, developed cardiomyopathy, and aggravated ischemia-induced heart failure. Mechanistically, we found that NRP-1 specifically controls peroxisome proliferator-activated receptor γ coactivator 1 α and peroxisome proliferator-activated receptor γ in cardiomyocytes through crosstalk with Notch1 and Smad2 signaling pathways, respectively. Moreover, SM22-α-Nrp-1 KO mice exhibited impaired physical activities and altered metabolite levels in serum, liver, and adipose tissues, as demonstrated by global metabolic profiling analysis.

CONCLUSIONS:

Our findings provide new insights into the cardioprotective role of NRP-1 and its influence on global metabolism.

KEYWORDS:

cardiomyopathies; metabolomics; mitochondria; myocardial infarction; myocytes, cardiac; neuropilin-1

PMID:
25882068
PMCID:
PMC4441604
DOI:
10.1161/ATVBAHA.115.305566
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Atypon Icon for PubMed Central
Loading ...
Support Center