TY - JOUR
T1 - Cardiomyopathy and Worsened Ischemic Heart Failure in SM22-α Cre-Mediated Neuropilin-1 Null Mice
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 A.
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 N.
AU - Simons, Michael
AU - Terzic, Andre
AU - Maulik, Nilanjana
AU - Mukhopadhyay, Debabrata
PY - 2015/6/27
Y1 - 2015/6/27
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.
AB - 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.
KW - cardiomyopathies
KW - metabolomics
KW - mitochondria
KW - myocardial infarction
KW - myocytes, cardiac
KW - neuropilin-1
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UR - http://www.scopus.com/inward/citedby.url?scp=84933041801&partnerID=8YFLogxK
U2 - 10.1161/ATVBAHA.115.305566
DO - 10.1161/ATVBAHA.115.305566
M3 - Article
C2 - 25882068
AN - SCOPUS:84933041801
SN - 1079-5642
VL - 35
SP - 1401
EP - 1412
JO - Arteriosclerosis, thrombosis, and vascular biology
JF - Arteriosclerosis, thrombosis, and vascular biology
IS - 6
ER -