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 A. 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

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

Keywords

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

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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    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. A., 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