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 Chini & 4 others Michael Simons, Andre Terzic, Nilanjana Maulik, Debabrata Mukhopadhyay

Research output: Contribution to journalArticle

13 Citations (Scopus)

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

Fingerprint

Neuropilin-1
Cardiomyopathies
Homeostasis
Heart Failure
Peroxisome Proliferator-Activated Receptors
Cardiac Myocytes
Vascular Smooth Muscle
Smooth Muscle Myocytes
Cardiomegaly
Adipose Tissue
Ischemia
Membranes
Liver
Serum

Keywords

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

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Cardiomyopathy and Worsened Ischemic Heart Failure in SM22-α Cre-Mediated Neuropilin-1 Null Mice : Dysregulation of PGC1α and Mitochondrial Homeostasis. / Wang, Ying; Cao, Ying; Yamada, Satsuki; Thirunavukkarasu, Mahesh; Nin, Veronica; Joshi, Mandip; Rishi, Muhammed T.; Bhattacharya, Santanu; Camacho-Pereira, Juliana; Sharma, Anil K.; Shameer, Khader; Kocher, Jean-Pierre; Sanchez, Juan A.; Wang, Enfeng; Hoeppner, Luke H.; Dutta, Shamit K.; Leof, Edward B; Shah, Vijay; Claffey, Kevin P.; Chini, Eduardo Nunes; Simons, Michael; Terzic, Andre; Maulik, Nilanjana; Mukhopadhyay, Debabrata.

In: Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 35, No. 6, 27.06.2015, p. 1401-1412.

Research output: Contribution to journalArticle

Wang, Y, Cao, Y, Yamada, S, Thirunavukkarasu, M, Nin, V, Joshi, M, Rishi, MT, Bhattacharya, S, Camacho-Pereira, J, Sharma, AK, Shameer, K, Kocher, J-P, Sanchez, JA, Wang, E, Hoeppner, LH, Dutta, SK, Leof, EB, Shah, V, Claffey, KP, Chini, EN, Simons, M, Terzic, A, Maulik, N & 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, vol. 35, no. 6, pp. 1401-1412. https://doi.org/10.1161/ATVBAHA.115.305566
Wang, Ying ; Cao, Ying ; Yamada, Satsuki ; Thirunavukkarasu, Mahesh ; Nin, Veronica ; Joshi, Mandip ; Rishi, Muhammed T. ; Bhattacharya, Santanu ; Camacho-Pereira, Juliana ; Sharma, Anil K. ; Shameer, Khader ; Kocher, Jean-Pierre ; Sanchez, Juan A. ; Wang, Enfeng ; Hoeppner, Luke H. ; Dutta, Shamit K. ; Leof, Edward B ; Shah, Vijay ; Claffey, Kevin P. ; Chini, Eduardo Nunes ; Simons, Michael ; Terzic, Andre ; Maulik, Nilanjana ; Mukhopadhyay, Debabrata. / Cardiomyopathy and Worsened Ischemic Heart Failure in SM22-α Cre-Mediated Neuropilin-1 Null Mice : Dysregulation of PGC1α and Mitochondrial Homeostasis. In: Arteriosclerosis, Thrombosis, and Vascular Biology. 2015 ; Vol. 35, No. 6. pp. 1401-1412.
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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.",
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T2 - Dysregulation of PGC1α and Mitochondrial Homeostasis

AU - Wang, Ying

AU - Cao, Ying

AU - Yamada, Satsuki

AU - Thirunavukkarasu, Mahesh

AU - Nin, Veronica

AU - Joshi, Mandip

AU - Rishi, Muhammed T.

AU - Bhattacharya, Santanu

AU - Camacho-Pereira, Juliana

AU - Sharma, Anil K.

AU - Shameer, Khader

AU - Kocher, Jean-Pierre

AU - Sanchez, Juan A.

AU - Wang, Enfeng

AU - Hoeppner, Luke H.

AU - Dutta, Shamit K.

AU - Leof, Edward B

AU - Shah, Vijay

AU - Claffey, Kevin P.

AU - Chini, Eduardo Nunes

AU - Simons, Michael

AU - Terzic, Andre

AU - Maulik, Nilanjana

AU - Mukhopadhyay, Debabrata

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N2 - 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.

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KW - metabolomics

KW - mitochondria

KW - myocardial infarction

KW - myocytes, cardiac

KW - neuropilin-1

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