Induction Of Cardiac Hypertrophy Research Articles

Direct and indirect effects of fibroblast growth factor 23 on the heart.

Fibroblast growth factor (FGF)23 is a bone-derived phosphotropic hormone that regulates phosphate and mineral homeostasis. Recent studies have provided evidence that a high plasma concentration of FGF23 is associated with cardiac disease, including left ventricular hypertrophy (LVH), heart failure, atrial fibrillation, and cardiac death. Experimental studies have shown that FGF23 activates fibroblast growth factor receptor 4 (FGFR4)/phospholipase Cγ/calcineurin/nuclear factor of activated T-cells signaling in cardiomyocytes and induces cardiac hypertrophy in rodents. Activation of FGFR4 by FGF23 normally requires the co-receptor α-klotho, and klotho-independent signaling occurs only under conditions characterized by extremely high FGF23 concentrations. Recent studies have demonstrated that FGF23 activates the renin-angiotensin-aldosterone system (RAAS) and induces LVH, at least in part as a result of lower vitamin D activation. Moreover, crosstalk between FGF23 and RAAS results in the induction of cardiac hypertrophy and fibrosis. In this review, we summarize the results of studies regarding the relationships between FGF23 and cardiac events, and describe the potential direct and indirect mechanisms whereby FGF23 induces LVH.

G Protein-Coupled Receptors-Receptors With New Tricks Up Their Sleeves.

G Protein-Coupled Receptors-Receptors With New Tricks Up Their Sleeves.

ROLE OF GSK-3 IN THE PATHOGENESIS OF CORONARY HEART DISEASE

Cardiovascular disease is the leading cause of morbidity and mortality worldwide. A strategy for early diagnosis of cardiovascular disease can help reduce the number of complications and deaths in patients. Research by the world's leading scientists is aimed at studying the pathogenetic links underlying the development of heart disease. The study of the molecular signaling pathways responsible for the induction of cardiac hypertrophy is of great clinical interest, and the potential therapeutic use of these molecules could prevent or slow down pathological myocardial remodeling and heart failure leading to cardiomyocyte death or dysfunction. The article discusses the influence of the components of the immune system on the pathogenesis of cardiovascular diseases. The role of GSK-3 kinase, which plays an important role in the regulation of proliferation, differentiation, apoptosis, and metabolic processes in the cell, as well as participates in the regulation of various signaling pathways, including Wnt / β-catenin and TGF-β-signaling, has been evaluated. Serum levels of GSK-3α and GSK-3β, as well as pro- and anti-inflammatory cytokines (IL-1β, IL-10 and TNF-α) were assessed in patients with coronary artery disease (myocardial infarction and unstable angina pectoris) and relatively healthy persons. The relationship of these indicators with clinical and laboratory data has been analyzed. The results obtained indicate the important role of immune processes in the pathogenesis of coronary heart disease. The performed combinatorial analysis of glycogen synthase kinase 3, serum cytokines with laboratory data (leukocyte and LDL levels) can help assess the severity of coronary heart disease and can help in determining risk stratification in patients with angina pectoris.

Abstract P144: Local Signaling And Cardiac Hypertrophy:specificity In The Face Of Pleiotropy

Rationale: Most likely, the overall myocyte cell growth during the pathological state of cardiac hypertrophy is regulated by a local muscle A-kinase anchoring protein β (mAKAPβ) complex. The mAKAPβ may act as a significant coordinator of myocyte hypertrophic signals. It may critically integrate the hypertrophic signals due to β-adrenergic and leukemia inhibitory factor (LIF)/gp-130 receptor stimulation. Observations suggest that mAKAPβ signalosome may act as a gate-keeper for regulating nuclear factor of activated T cells (NFATc) activity and nuclear localization of this complex might be directly linked to the induction of cardiac hypertrophy. The mAKAPβ complex might function through modulating the profiles of a local cyclic adenosine 3’,5’ monophosphate (cAMP) microdomain at perinuclear region in cardiomyocytes. The acute stimulation of cAMP may be beneficial for the heart, whereas chronic stimulation might cause damage. The transition between the chronic and acute function of cAMP is probably modulated by the ability of myocytes to tightly regulate the cAMP levels in local microdomains across the cell. Any dysfunction in this process may lead to net accumulation and a global rise of cAMP levels, leading to deleterious effects on the heart. Objective: cAMP is a single messenger but delivers multiple messages in myocytes. How is this managed? Here, we aim to investigate a key question that how mAKAPβ signalosome might ensure the microdomain specificity despite the pleiotropic nature of the second messenger. Methods and Results: Our results may explain how, in the context of hypertrophy, mAKAPβ complex coordinates the interactions between two coupled cAMP-induced feedback loops and LIF-induced activation of the MAPK pathway. Our results may also explain that mAKAPβ complex functions through anchoring protein kinase A (PKA) and ERK5 in the signalosome thus, modulating the bidirectional regulation of phosphodiesterase and hence the control of localized cAMP metabolism as well as the shape and temporal profile of the second messenger in a specific domain. Conclusion: Here, we propose a mechanistic model which suggests that stress-induced reprofiling of cAMP flux at discrete cellular locations may lead to cardiovascular disease.

The β2-Subunit of Voltage-Gated Calcium Channels Regulates Cardiomyocyte Hypertrophy.

L-type voltage-gated calcium channels (LTCCs) regulate crucial physiological processes in the heart. They are composed of the Cavα1 pore-forming subunit and the accessory subunits Cavβ, Cavα2δ, and Cavγ. Cavβ is a cytosolic protein that regulates channel trafficking and activity, but it also exerts other LTCC-independent functions. Cardiac hypertrophy, a relevant risk factor for the development of congestive heart failure, depends on the activation of calcium-dependent pro-hypertrophic signaling cascades. Here, by using shRNA-mediated Cavβ silencing, we demonstrate that Cavβ2 downregulation enhances α1-adrenergic receptor agonist-induced cardiomyocyte hypertrophy. We report that a pool of Cavβ2 is targeted to the nucleus in cardiomyocytes and that the expression of this nuclear fraction decreases during in vitro and in vivo induction of cardiac hypertrophy. Moreover, the overexpression of nucleus-targeted Cavβ2 in cardiomyocytes inhibits in vitro-induced hypertrophy. Quantitative proteomic analyses showed that Cavβ2 knockdown leads to changes in the expression of diverse myocyte proteins, including reduction of calpastatin, an endogenous inhibitor of the calcium-dependent protease calpain. Accordingly, Cavβ2-downregulated cardiomyocytes had a 2-fold increase in calpain activity as compared to control cells. Furthermore, inhibition of calpain activity in Cavβ2-downregulated cells abolished the enhanced α1-adrenergic receptor agonist-induced hypertrophy observed in these cells. Our findings indicate that in cardiomyocytes, a nuclear pool of Cavβ2 participates in cellular functions that are independent of LTCC activity. They also indicate that a downregulation of nuclear Cavβ2 during cardiomyocyte hypertrophy promotes the activation of calpain-dependent hypertrophic pathways.

RAAV9-Mediated MEK1 Gene Expression Restores Post-conditioning Protection Against Ischemia Injury in Hypertrophic Myocardium.

We investigated whether increased expression of activated mitogen-activated protein kinase (MAPK) kinases 1 (MEK1) restores ischemic post-conditioning (IPostC) protection in hypertrophic myocardium following ischemia/reperfusion (I/R) injury. C57Bl/6 mice received recombinant adeno-associated virus type 9 (rAAV9)-mediated activated MEK1 gene delivery systemically, then following the induction of cardiac hypertrophy via transverse aortic constriction for 4weeks. In a Langendorff model, hypertrophic hearts were subjected to 40min/60min I/R or with IPostC intervention consisting of 6cycles of 10s reperfusion and 10s no-flow before a 60-min reperfusion. Hemodynamics, infarct size (IS), myocyte apoptosis and changes in expression of reperfusion injury salvage kinase (RISK) pathway were examined. rAAV9-MEK1 gene delivery led to a 4.3-fold and 2.7-fold increase in MEK1 mRNA and protein expression in the heart versus their control values. I/R resulted in a larger IS in hypertrophic than in non-hypertrophic hearts (52.3 ± 4.7% vs. 40.0 ± 2.5%, P < 0.05). IPostC mediated IS reduction in non-hypertrophic hearts (27.6 ± 2.6%, P < 0.05), while it had no significant effect in hypertrophic hearts (46.5 ± 3.1%, P=NS) compared with the IS in non-hypertrophic or hypertrophic hearts subjected to I/R injury only, respectively. Hemodynamic decline induced by I/R was preserved by IPostC in non-hypertrophic hearts but not in hypertrophic hearts. rAAV9-MEK1 gene delivery restored IPostC protection in hypertrophic hearts evidenced by reduced IS (32.0 ± 2.8% vs. 46.5 ± 3.1%) and cardiac cell apoptosis and largely preserved hemodynamic parameters. These protective effects were associated with significantly increased phosphorylation of ERK1/2 and ribosomal protein S6 kinases (p70S6K), but it had no influence on Akt and glycogen synthase kinase-3β. These results demonstrated that rAAV9-mediated activated MEK1 expression restores IPostC protection in the hypertrophic heart against I/R injury through the activation of ERK pathway.

ITRAQ‑based quantitative proteomics analysis of the potential application of secretoneurin gene therapy for cardiac hypertrophy induced by DL‑isoproterenol hydrochloride in mice.

A previous study by our group demonstrated a protective role of the neuropeptide secretoneurin (SN) in DL-isoproterenol hydrochloride (ISO)-induced cardiac hypertrophy in mice. To further characterize the molecular mechanism of SN treatment, an isobaric tags for relative and absolute quantification (iTRAQ)-based quantitative proteomic analysis was applied to identify putative target proteins and molecular pathways. An SN expression vector was injected into the myocardial tissues of mice, and the animals were then subcutaneously injected with ISO (5 mg/kg/day) for 7 days to induce cardiac hypertrophy. The results of echocardiography and hemodynamic measurements indicated that the function of the heart impaired by ISO treatment was significantly ameliorated via SN gene injection. The investigation of heart proteomics was performed by iTRAQ-based liquid chromatography-tandem mass spectrometry analysis. A total of 2,044 quantified proteins and 15 differentially expressed proteins were associated with SN overexpression in mice with cardiac hypertrophy. Functional enrichment analysis demonstrated that these effects were possibly associated with metabolic processes. A protein-protein interaction network analysis was constructed and the data indicated that apolipoprotein C-III (Apoc3) was associated with the positive effect of SN on the induction of cardiac hypertrophy in mice. The present study proposed a potential mechanism of SN action on Apoc3 upregulation that may contribute to the amelioration of cardiac hypertrophy. These findings can aid the clinical application of SN in patients with cardiac hypertrophy.

Effective Delivery of Hypertrophic miRNA Inhibitor by Cholesterol-Containing Nanocarriers for Preventing Pressure Overload Induced Cardiac Hypertrophy.

Persistent cardiac hypertrophy causes heart failure and sudden death. Gene therapy is a promising intervention for this disease, but is limited by the lack of effective delivery systems. Herein, it is reported that CHO‐PGEA (cholesterol (CHO)‐terminated ethanolamine‐aminated poly(glycidyl methacrylate)) can efficiently condense small RNAs into nanosystems for preventing cardiac hypertrophy. CHO‐PGEA contains two features: 1) lipophilic cholesterol groups enhance transfection efficiency in cardiomyocytes, 2) abundant hydrophilic hydroxyl groups benefit biocompatibility. miR‐182, which is known to downregulate forkhead box O3, is selected as an intervention target and can be blocked by synthetic small RNA inhibitor of miR‐182 (miR‐182‐in). CHO‐PGEA can efficiently deliver miR‐182‐in into hearts. In the mice with aortic coarctation, CHO‐PEGA/miR‐182‐in significantly suppresses cardiac hypertrophy without organ injury. This work demonstrates that CHO‐PGEA/miRNA nanosystems are very promising for RNA‐based therapeutics to treat heart diseases.

Xanthine Oxidase Inhibitor, Febuxostat Ameliorates the High Salt Intake-Induced Cardiac Hypertrophy and Fibrosis in Dahl Salt-Sensitive Rats.

Xanthine oxidase (XO) is a source of reactive oxygen species production in the heart. However, pathophysiological role of XO has not been clarified in hypertensive heart disease. Thus, the present study examined the impacts of high salt (HS) intake and febuxostat (Fx), a XO inhibitor in Dahl salt-sensitive (Dahl-S) rats. Eight-week old, male Dahl-S rats were fed a normal salt diet (0.6% NaCl) or a HS diet (8% NaCl) for 8 weeks. A part of the rats fed the HS diet were simultaneously treated with Fx (3 mg/kg/day). HS intake increased blood pressure and heart weight with cardiomyocyte hypertrophy and interstitial fibrosis in the left ventricle (LV), and Fx diminished them. HS increased the XO activity 4.7-fold and nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase activity 1.5-fold, and Fx not only blocked the XO activity but also inhibited the HS-increased NADPH oxidase activity. HS increased the expression of XO, collagen, transforming growth factor-β1 (TGF-β1), angiotensin-converting enzyme, and angiotensin II type 1 receptor and the phosphorylation of extracellular signal-regulated kinase (ERK) in the LV, and Fx reduced the expression and phosphorylation of these proteins except XO. Fx ameliorates the HS intake-induced hypertension, LV hypertrophy, and fibrosis with decreasing the TGF-β1 expression and ERK phosphorylation in Dahl-S rats. Fx also down-regulates cardiac NADPH oxidase and renin-angiotensin system. The XO inhibition may be an effective therapy for hypertensive heart disease.

MiR-376b-3p attenuates mitochondrial fission and cardiac hypertrophy by targeting mitochondrial fission factor.

Mitochondrial dysfunction contributes to the pathogenesis of cardiac hypertrophy. The disequilibrium of mitochondrial dynamic, which refers to mitochondrial fusion and fission, leads to mitochondrial morphology alteration and dysfunction. Enhanced understanding of the molecular mechanisms in depth may shed light on the therapy of the disease. In this study, we show that mitochondrial fission factor (MFF) is up-regulated upon hypertrophic agonist noradrenaline (NA) treatment. Knockdown of MFF attenuated NA induced mitochondrial fission and cardiac hypertrophy. Mitochondrial fission factor is a direct target of miR-376b-3p, which attenuated expression enhanced MFF expression through binding to its 3'UTR. Expression of miR-376b-3p weakened the fragmentation of mitochondria as well as decreased hypertrophic response through regulating MFF in NA treated neonatal rat ventricular cells (NRVCs). This study suggested that miR-376b-3p is a novel modulator affecting mitochondrial morphology through targeting MFF.

Maternal NO2 exposure induces cardiac hypertrophy in male offspring via ROS-HIF-1α transcriptional regulation and aberrant DNA methylation modification of Csx/Nkx2.5.

Maternal exposure to nitrogen dioxide (NO2) poses a risk for morbidity and mortality in infantile congenital heart diseases and even adult cardiovascular diseases. However, the experimental evidence supporting these effects is insufficient, and the related regulatory mechanisms are unknown. In the present study, we aimed to determine whether maternal NO2 exposure causes cardiac hypertrophy-related consequences in offspring, and if so, how these adverse effects occur in the postnatal heart. The results indicate that in mice, maternal NO2 exposure causes cardiac hypertrophy in male offspring. This altered phenotype was accompanied by increased expression of atrial natriuretic peptide, B-type natriuretic peptide, bone morphogenetic protein 10 and β-myosin heavy chain and elevated activities of cardiomyocyte injury markers, including serum glutamate-oxaloacetate transaminase, lactate dehydrogenase and kinases creatine phosphokinase (CK-MB) in serum. The cardiac-specific transcription factor Csx/Nkx2.5 played an important role in the induction of cardiac hypertrophy and cardiomyocyte injury, and the action was associated with ROS-HIF-1α transcriptional regulation and DNA hypomethylation modification.

MuRF1 mono-ubiquitinates TR[alpha] to inhibit T3 induced cardiac hypertrophy in vivo

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

(1176) - Non-Nucleosidic DNA Methyl Transferase Inhibition Attenuates Pressure Overload Induced Cardiac Hypertrophy in Rats

(1176) - Non-Nucleosidic DNA Methyl Transferase Inhibition Attenuates Pressure Overload Induced Cardiac Hypertrophy in Rats

ZNF307 (Zinc Finger Protein 307) Acts as a Negative Regulator of Pressure Overload-Induced Cardiac Hypertrophy.

Pathological cardiac hypertrophy is a key risk factor for heart failure. We found that the protein expression levels of the ZNF307 (zinc finger protein 307) were significantly increased in heart samples from both human patients with dilated cardiomyopathy and mice subjected to aortic banding. Therefore, we aimed to elucidate the role of ZNF307 in the development of cardiac hypertrophy and to explore the signal transduction events that mediate the effect of ZNF307 on cardiac hypertrophy, using cardiac-specific ZNF307 transgenic (ZNF307-TG) mice and ZNF307 global knockout (ZNF307-KO) mice. The results showed that the deletion of ZNF307 potentiated aortic banding-induced pathological cardiac hypertrophy, fibrosis, and cardiac dysfunction; however, the aortic banding-induced cardiac hypertrophic phenotype was dramatically diminished by ZNF307 overexpression in mouse heart. Mechanistically, the antihypertrophic effects mediated by ZNF307 in response to pathological stimuli were associated with the direct inactivation of NF-κB (nuclear factor-κB) signaling and blockade of the nuclear translocation of NF-κB subunit p65. Furthermore, the overexpression of a degradation-resistant mutant of IκBα (IκBαS32A/S36A) reversed the exacerbation of cardiac hypertrophy, fibrosis, and dysfunction shown in aortic banding-treated ZNF307-KO mice. In conclusion, our findings demonstrate that ZNF307 ameliorates pressure overload-induced cardiac hypertrophy by inhibiting the activity of NF-κB-signaling pathway.

Non-Nucleoside DNA Methyltransferase Inhibition Attenuates Pressure Overload Induced Cardiac Hypertrophy in Rats

Non-Nucleoside DNA Methyltransferase Inhibition Attenuates Pressure Overload Induced Cardiac Hypertrophy in Rats

Abstract 260: Systemic Loss of p62 Reduces Pressure Overload Induced Cardiac Hypertrophy, Dysfunction and Apoptosis

Introduction: p62 is a pleiotropic protein with defined roles in TNFα signaling, protein aggregate formation, and protein degradation processes. Current data suggest that p62 is a stress-response protein, with increased protein levels reported in TAC, MI, I/R, and protein aggregation models of cardiac disease. To date, there has been little study on the gain- or loss- of p62 function in cardiomyocyte/cardiac pathology. Our preliminary data found that adenoviral overexpression of p62 caused cardiomyocyte hypertrophy and cytotoxicity and that p62 was upregulated by pressure-overload stress. Hypothesis: Loss of p62 will be cardioprotective against pressure-overload pathology. Methods: Systemic p62 knockout mice underwent sham or transverse-aortic constriction surgery and were studied longitudinally to 8 weeks post-surgery by echocardiography. Results: Hearts from p62-null mice had significantly preserved cardiac function (%Fractional Shortening) over wild-type controls. p62-deficient mice had significantly less cardiac hypertrophy (heart weight/body weight ratios and myofiber cross-sectional areas) and showed no chamber dilation (LVED) in response to pressure-overload stress, unlike wild-types. Hearts from wild-type mice showed pronounced fibrotic remodeling and induction of apoptosis (TUNEL), while p62 knockouts had significantly less collagen staining and no evidence of apoptotic stimulation. Overexpression of p62 in rat neonatal cardiomyocytes significantly inhibited proteasomal catalytic activities (&gt;50%) and showed increased indices of cardiomyocyte cell death. Conclusion: Our data show that induction of p62 is deleterious in vitro and that loss of p62 imparts cardioprotection against hemodynamic stress in vivo . The beneficial phenotype observed in hearts from p62-deficient mice may be due to p62-dependent mechanisms responsible for proteasomal dysfunction and apoptosis activation.

Abundant and Altered Expression of PIWI-Interacting RNAs during Cardiac Hypertrophy.

The discovery of PIWI-interacting RNAs (piRNAs) has fundamentally changed our understanding of post transcriptional regulation of transposons and other genes. Unlike miRNA and siRNA, the piRNAs are the most abundant but least studied RNA species in mammals. Although the expression of PIWI proteins and piRNAs has long been regarded as germline specific, increasing evidences suggest the expression of piRNAs in somatic cells. In this study, the small RNA sequencing executed during induction of cardiac hypertrophy in both in vivo and in vitro conditions were annotated for the expression of piRNAs. The expression of piRNAs was validated by qPCR and RNA immunoprecipitation. In addition, the presence of piRNAs in circulation of myocardial infarction patients was studied by qPCR. We identified an abundant and altered expression of piRNAs during cardiac hypertrophy. The differentially expressed piRNAs was validated by qPCR and RNA immunoprecipitation. The significantly and differentially expressed piRNAs were predicted to target different retrotransposons and mRNAs in the rat genome. The detection of specific piRNA in serum of myocardial infarction patients suggests the potential of piRNA for diagnosis. Overall this study is the first to provide a whole-genome analysis of the large repertoire of piRNAs in the cardiac system and this would pave a new path to understanding the molecular aetiology of piRNA and retrotransposons in the physiology and pathology of the cardiac system.

Midkine Deteriorates Cardiac Remodeling via Epidermal Growth Factor Receptor Signaling in Chronic Kidney Disease.

In chronic kidney disease, activation of the epidermal growth factor receptor (EGFR) leads to cardiac hypertrophy, which affects morbidity and mortality. In patients with renal insufficiency and heart failure, the expression of midkine, a heparin-binding growth factor, is increased. Therefore, we investigated the association between midkine and EGFR in the induction of cardiac hypertrophy and dysfunction in chronic kidney disease. We performed subtotal nephrectomies in midkine-knockout mice and wild-type mice. We found that subtotal nephrectomy-induced cardiac hypertrophy and phosphorylation of extracellular signal-regulated kinase 1/2 and AKT were attenuated in midkine-knockout mice compared with wild-type mice. An antiphosphotyrosine receptor antibody array was used to demonstrate that EGFR phosphorylation in the heart was also lower in midkine-knockout mice than in wild-type mice. Midkine induced EGFR, extracellular signal-regulated kinase 1/2, and AKT phosphorylation and led to hypertrophy in neonatal rat cardiomyocytes. Pretreatment with EGFR inhibitors or EGFR silencing suppressed midkine-stimulated phosphorylation of extracellular signal-regulated kinase 1/2 and AKT, induction of fetal cardiac gene expression, and hypertrophy in cardiomyocytes. To confirm the association between midkine and EGFR in vivo, mice subjected to subtotal nephrectomy were treated with the EGFR inhibitor gefitinib. Gefitinib treatment attenuated subtotal nephrectomy-induced cardiac hypertrophy. These results indicate that midkine might be a key mediator of cardiorenal interactions through EGFR activation, which plays a crucial role in cardiac hypertrophy in chronic kidney disease.

QiShenYiQi Pills, a compound in Chinese medicine, protects against pressure overload-induced cardiac hypertrophy through a multi-component and multi-target mode.

The present study aimed to explore the holistic mechanism for the antihypertrophic effect of a compound in Chinese medicine, QiShenYiQi Pills (QSYQ) and the contributions of its components to the effect in rats with cardiac hypertrophy (CH). After induction of CH by ascending aortic stenosis, rats were treated with QSYQ, each identified active ingredient (astragaloside IV, 3, 4-dihydroxy-phenyl lactic acid or notoginsenoside R1) from its 3 major herb components or dalbergia odorifera, either alone or combinations, for 1 month. QSYQ markedly attenuated CH, as evidenced by echocardiography, morphology and biochemistry. Proteomic analysis and western blot showed that the majority of differentially expressed proteins in the heart of QSYQ-treated rats were associated with energy metabolism or oxidative stress. Each ingredient alone or their combinations exhibited similar effects as QSYQ but to a lesser extent and differently with astragaloside IV and notoginsenoside R1 being more effective for enhancing energy metabolism, 3, 4-dihydroxy-phenyl lactic acid more effective for counteracting oxidative stress while dalbergia odorifera having little effect on the variables evaluated. In conclusion, QSYQ exerts a more potent antihypertrophic effect than any of its ingredients or their combinations, due to the interaction of its active components through a multi-component and multi-target mode.

Cardiomyopathy and Worsened Ischemic Heart Failure in SM22-α Cre-Mediated Neuropilin-1 Null Mice: Dysregulation of PGC1α and Mitochondrial Homeostasis.

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. 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. Our findings provide new insights into the cardioprotective role of NRP-1 and its influence on global metabolism.