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 Kocher, Juan A. Sanchez, Enfeng Wang, Luke H. Hoeppner, Shamit K. Dutta, Edward B Leof, Vijay Shah, Kevin P. Claffey, Eduardo Nunes ChiniMichael Simons, Andre Terzic, Nilanjana Maulik, Debabrata Mukhopadhyay

Research output: Contribution to journalArticle

14 Scopus citations

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
StatePublished - Jun 27 2015

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Keywords

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

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Wang, Y., Cao, Y., Yamada, S., Thirunavukkarasu, M., Nin, V., Joshi, M., Rishi, M. T., Bhattacharya, S., Camacho-Pereira, J., Sharma, A. K., Shameer, K., Kocher, J-P., Sanchez, J. A., Wang, E., Hoeppner, L. H., Dutta, S. K., Leof, E. B., Shah, V., Claffey, K. P., ... Mukhopadhyay, D. (2015). Cardiomyopathy and Worsened Ischemic Heart Failure in SM22-α Cre-Mediated Neuropilin-1 Null Mice: Dysregulation of PGC1α and Mitochondrial Homeostasis. Arteriosclerosis, Thrombosis, and Vascular Biology, 35(6), 1401-1412. https://doi.org/10.1161/ATVBAHA.115.305566