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

Ying Wang, Ying Cao, Satsuki Yamada, Mahesh Thirunavukkarasu, Veronica Nin, Mandip Joshi, Muhammed T. Rishi, Santanu Bhattacharya, Juliana Camacho-Pereira, Anil K. Sharma, Khader Shameer, Jean Pierre A Kocher, Juan Sanchez, Enfeng Wang, Luke H. Hoeppner, Shamit K. Dutta, Edward B. Leof, Vijay Shah, Kevin P. Claffey, Eduardo N. ChiniMichael Simons, Andre Terzic, Nilanjana Maulik, Debabrata Mukhopadhyay

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1401-1412
Number of pages12
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume35
Issue number6
DOIs
Publication statusPublished - Jun 27 2015
Externally publishedYes

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Keywords

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

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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