Cardiomyopathy and Worsened Ischemic Heart Failure in SM22-α Cre-Mediated Neuropilin-1 Null Mice

Abstract

Objective Neuropilin-1 (NRP-1) is a multi-domain 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 (PGC1α) in cardiomyocytes (CMs) and vascular smooth muscle cells (VSMCs), 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 CMs and VSMCs (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 PGC1α and PPARγ in CMs 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 cardio-protective role of NRP-1 and its influence on global metabolism.

Differential Regulation of Cardiac Function and Intracardiac Cytokines by Rapamycin in Healthy and Diabetic Rats

“…These include IL-10 and decorin that ameliorates high fat diet-induced cardiac dysfunction [29, 37], neuropilin that attenuates cardiomyopathy [38], and LIX (CXCL-5) that has a protective role in coronary artery disease [39]; see Figure 4. Other suppressed anti-inflammatory markers in the hearts of ZO-C include interferon- γ (IFN- γ ) that has cardioprotective roles and Platelet Derived Growth Factor (PDGF AA) that improves wound healing [40, 41].…”

Cardiomyocyte and Vascular Smooth Muscle-Independent 11β-Hydroxysteroid Dehydrogenase 1 Amplifies Infarct Expansion, Hypertrophy, and the Development of Heart Failure After Myocardial Infarction in Male Mice

“…All experiments involving animals were approved by The University of Edinburgh Animal Welfare and Ethical Review Body and by the Unite Kingdom Home Office. Experiments used adult male (10–14 wk of age) mice with global deficiency on a C57Bl/6 genetic background ( Hsd11b1 −/− ) ( 8 , 20 ), with C57Bl/6 controls, or mice in which deletion was targeted to vascular smooth muscle and cardiomyocytes ( 21 , 22 ). These Hsd11b1 fl/fl Sm22 α -Cre + ( Hsd11b1 CVCre+ ) were generated by crossing Sm22 α -Cre mice with Hsd11b1 fl/fl mice, homozygous for a “floxed” allele of Hsd11b1 (generated by Artemis Pharmaceuticals directly onto a C57BL/6J background).…”

Metabolic Flexibility and Dysfunction in Cardiovascular Cells

“…One theory is that excess mitochondrial activity and ROS production is responsible in part for cardiomyopathy and sudden cardiac death due to arrhythmia. 60 This concept is supported by a recent study by Wang and colleagues in ATVB , 61 demonstrating that mice deficient in neuropilin-1 in cardiomyocytes and smooth muscle cells exhibited cardiomyopathy associated with increased mitochondrial content and aggravated ischemia-induced heart failure. Thus, neurpilin-1, a receptor that binds several structurally distinct ligands, including VEGF and TGF-β, maintains mitochondrial homeostasis in the failing heart.…”