Role of Dipeptidylpeptidase-4 in the Cardiac Remodeling Observed in Chronic Heart Failure Induced by Pressure Overload

Background: Hepatokine selenoprotein P (SeP) contributes to insulin resistance and hyperglycemia in patients with type 2 diabetes. Although clinical studies suggest the insulin resistance is an independent risk factor of heart failure and inhibition of SeP protects the heart from ischemia reperfusion injury, the role of SeP in pathogenesis of chronic heart failure is not well understood. Objective: We examined the role of SeP in the regulation of cardiac remodeling in response to pressure overload. Methods and Results: We measured serum SeP levels in 22 patients for heart failure with reduced ejection fraction (HFrEF; LVEF<50%) and 22 normal subjects. Serum levels of SeP were significantly elevated in patients with HFrEF compared to in normal subjects (3.55 ± 0.43 vs 2.98 ± 0.43, p<0.01). To examine the role of SeP in cardiac remodeling, SeP knockout (KO) and wild-type (WT) mice were subjected to pressure overload (transverse aortic constriction (TAC)) for 2 weeks. The mortality rate following TAC was significantly decreased in SeP KO mice compared to WT mice (22.5 % in KO mice (n=40) vs 52.3 % in WT mice (n=39) p<0.01). LV weight/tibial length (TL) was significantly smaller in SeP KO mice than in WT mice (6.75 ± 0.24 vs 8.33 ± 0.32, p<0.01). Lung weight/TL was significantly smaller in SeP KO than in WT mice (10.46 ± 0.44 vs 16.38 ± 1.12, p<0.05). Interestingly, hepatic expression of SeP in WT was significantly increased by TAC. To determine whether hepatic overexpression of SeP affects TAC-induced cardiac hypertrophy, a hydrodynamic injection method was used to generate mice that overexpress SeP mRNA in the liver. Hepatic overexpression of SeP in SeP KO mice lead to a significant increase in LV weight/TL and Lung weight/TL after TAC compared to that in other SeP KO mice. Conclusions: These results suggest that serum levels of SeP were elevated in patients with heart failure with reduced ejection fraction and cardiac pressure overload induced hepatic expression of SeP in mice model. Gene deletion of SeP attenuated cardiac hypertrophy and dysfunction in response to pressure overload in mice. SeP possibly plays a pivotal role in promoting cardiac remodeling through the liver-heart axis.

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Abstract 1271: IKKβ/NF-κB Pathway Protects Hearts from Hemodynamic Stress Mediated through Regulating MnSOD Expression

Circulation ◽

10.1161/circ.116.suppl_16.ii_259-b ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Shungo Hikoso ◽

Kinya Otsu ◽

Osamu Yamaguchi ◽

Toshihiro Takeda ◽

Masayuki Taniike ◽

...

Keyword(s):

Oxidative Stress ◽

Heart Failure ◽

Cardiac Remodeling ◽

Weight Ratio ◽

Pressure Overload ◽

Left Ventricular ◽

Negative Regulator ◽

Iκb Kinase ◽

Jnk Activation

Objectives: We have previously reported that NF-κB contributes to GPCR agonist-induced hypertrophy in cultured cardiomyocytes. However, the in vivo role of this pathway in the pathogenesis of cardiac remodeling remains to be elucidated. Although IκB kinase β (IKKβ)/NF-κB pathway is a major negative regulator of cell death, it can sensitize cells to death-inducing stimuli in some instances, thus it can be either anti- or pro-apoptotic. In this study, we aimed to clarify the role of IKKβ/NF-κB signaling in cardiac remodeling using cardiac-specific IKKβ deficient mice. Methods and Results: We crossed mice bearing an IKK β flox allele with mice expressing the Cre recombinase under the control of the myosin light chain 2v promoter ( MLC2v-Cre +/− ) to generate IKK β flox/flox ; MLC2v-Cre +/− mice (conditional knockout:CKO). Then, CKO mice (n=14) and control littermates bearing IKK β flox/flox (CTRL, n=14) were subjected to pressure overload by means of transverse aortic constriction (TAC). EMSA analysis revealed NF-κB DNA binding activity after TAC had attenuated in CKO hearts. One week after TAC, echocardiography showed significantly lower left ventricular fractional shortening (26.9±2.7% vs. 41.4±0.9%, p<0.01), and higher left ventricular end-diastolic dimension (4.02±0.14 mm vs. 3.47±0.08 mm, p<0.01) and lung weight/body weight ratio (11.1±1.4 vs. 5.5±0.1, p<0.01) in CKO mice compared with CTRL mice, indicating the development of heart failure in CKO mice. Number of apoptotic cells had increased in CKO hearts after TAC, suggesting that the enhanced apoptosis is a cause for heart failure. The expression levels of MnSOD mRNA and protein after TAC, which is one of NF-κB target genes, were significantly lower in CKO than those in CTRL mice. As a consequence, oxidative stress and JNK activation in CKO hearts after TAC had significantly increased compared with those in CTRL heart, suggesting that increased oxidative stress and enhanced JNK activity resulted in cardiomyocyte apoptosis in CKO hearts. Conclusion: These results show that IKKβ/NF-κB pathway in cardiomyocyte plays a protective role mediated through attenuation of oxidative stress and JNK activation in response to pressure overload.

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Autophagy modulation: a potential therapeutic approach in cardiac hypertrophy

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00145.2017 ◽

2017 ◽

Vol 313 (2) ◽

pp. H304-H319 ◽

Cited By ~ 37

Author(s):

Xuejun Wang ◽

Taixing Cui

Keyword(s):

Heart Failure ◽

Quality Control ◽

Cardiac Hypertrophy ◽

Cardiac Remodeling ◽

Pressure Overload ◽

Energy Crisis ◽

Pathogenic Role ◽

Evolutionarily Conserved ◽

Control Survival

Autophagy is an evolutionarily conserved process used by the cell to degrade cytoplasmic contents for quality control, survival for temporal energy crisis, and catabolism and recycling. Rapidly increasing evidence has revealed an important pathogenic role of altered activity of the autophagosome-lysosome pathway (ALP) in cardiac hypertrophy and heart failure. Although an early study suggested that cardiac autophagy is increased and that this increase is maladaptive to the heart subject to pressure overload, more recent reports have overwhelmingly supported that myocardial ALP insufficiency results from chronic pressure overload and contributes to maladaptive cardiac remodeling and heart failure. This review examines multiple lines of preclinical evidence derived from recent studies regarding the role of autophagic dysfunction in pressure-overloaded hearts, attempts to reconcile the discrepancies, and proposes that resuming or improving ALP flux through coordinated enhancement of both the formation and the removal of autophagosomes would benefit the treatment of cardiac hypertrophy and heart failure resulting from chronic pressure overload.

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Cytosolic DNA sensor cGAS plays an essential pathogenetic role in pressure overload-induced heart failure

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00097.2020 ◽

2020 ◽

Vol 318 (6) ◽

pp. H1525-H1537 ◽

Cited By ~ 2

Author(s):

Dan Hu ◽

Yu-Xia Cui ◽

Man-Yan Wu ◽

Long Li ◽

Li-Na Su ◽

...

Keyword(s):

Heart Failure ◽

Inflammatory Response ◽

Cardiac Remodeling ◽

Therapeutic Target ◽

Pressure Overload ◽

Dna Sensor ◽

Pathogenetic Role ◽

Early Inflammatory Response ◽

Sting Pathway

In this study, we first revealed a novel role of cGAS in the regulation of pathological cardiac remodeling and dysfunction upon pressure overload. We found that the cGAS/STING pathway was activated during pressure overload. Moreover, we also demonstrated that inhibition of the cGAS/STING pathway alleviated pathological cardiac remodeling and downregulated the early inflammatory response during pressure overload-induced HF. Together, these findings will provide a new therapeutic target for HF.

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Microfibrillar-Associated Protein 4 Regulates Stress-Induced Cardiac Remodeling

Circulation Research ◽

10.1161/circresaha.120.317146 ◽

2021 ◽

Author(s):

Lisa E Dorn ◽

William R Lawrence ◽

Jennifer Petrosino ◽

Xianyao Xu ◽

Thomas J Hund ◽

...

Keyword(s):

Heart Failure ◽

Cardiac Hypertrophy ◽

Cardiac Remodeling ◽

Matrix Protein ◽

Treatment Options ◽

Pressure Overload ◽

Extracellular Matrix Protein ◽

Cardiomyocyte Hypertrophy ◽

Hypertrophic Growth

Rationale: Cardiac hypertrophy, a major risk factor for heart failure, occurs when cardiomyocytes remodel in response to complex signaling induced by injury or cell stress. Although cardiomyocytes are the ultimate effectors of cardiac hypertrophy, non-myocyte populations play a large yet understudied role in determining how cardiomyocytes respond to stress. Objective: To identify novel paracrine regulators of cardiomyocyte hypertrophic remodeling. Methods and Results: : We have identified a novel role for a non-myocyte-derived and TGFbeta1-induced extracellular matrix protein Microfibrillar-associated protein 4 (MFAP4) in the pathophysiology of cardiac remodeling. We have determined that non-myocyte cells are the primary sources of MFAP4 in the heart in response to TGFbeta1 stimulation. Furthermore, we have demonstrated a crucial role of MFAP4 in the cardiac adaptation to stress. Global knockout of MFAP4 led to increased cardiac hypertrophy and worsened cardiac function following chronic pressure overload. Also, one week of angiotensin-mediated neurohumoral stimulation was sufficient to exacerbate cardiomyocyte hypertrophy in MFAP4 null mice. In contrast, administration of exogenous MFAP4 to isolated cardiomyocytes blunted their phenylephrine-induced hypertrophic growth through an integrin-dependent mechanism. Finally, MFAP4 deficiency leads to dysregulated integration of G protein-coupled receptor and integrin signaling in the heart. Conclusions: Altogether, our results demonstrate a critical paracrine role of MFAP4 in the development of cardiac hypertrophy and could inform future treatment options for heart failure patients.

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P2590A liver-derived secretory protein, selenoprotein P causes pressure overload-induced cardiac hypertrophys

European Heart Journal ◽

10.1093/eurheartj/ehz748.0916 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

S Usui ◽

S Takashima ◽

O Inoue ◽

C Goten ◽

Y Takeda ◽

...

Keyword(s):

Heart Failure ◽

Cardiac Hypertrophy ◽

Cardiac Remodeling ◽

Interstitial Fibrosis ◽

Ischemia Reperfusion ◽

Pressure Overload ◽

Selenoprotein P ◽

Lung Weight ◽

Hepatic Expression

Abstract Background Hepatokine selenoprotein P (SeP) contributes to insulin resistance and hyperglycemia in patients with type 2 diabetes. Inhibition of SeP protects the heart from ischemia reperfusion injury and serum levels of SeP are elevated in patients with heart failure with reduced ejection fraction. Objective We investigated the role of SeP in the regulation of cardiac remodeling in response to pressure overload. Methods and results To examine the role of SeP in cardiac remodeling, transverse aortic constriction (TAC) was subjected to SeP knockout (KO) and wild-type (WT) mice for 2 weeks. Hepatic expression of SeP in WT was significantly increased by TAC. LV weight/tibial length (TL) was significantly smaller in SeP KO mice than in WT mice (6.75±0.24 vs 8.33±0.32, p<0.01). Lung weight/TL was significantly smaller in SeP KO than in WT mice (10.46±0.44 vs 16.38±1.12, p<0.05). TAC-induced cardiac upregulation of the fetal type genes, including atrial and brain natriuretic factors, was significantly attenuated in SeP KO compared to WT. Furthermore, azan staining revealed that there was significantly less interstitial fibrosis in hearts after TAC in SeP KO than in WT mice. To determine whether hepatic overexpression of SeP affects TAC-induced cardiac hypertrophy, a hydrodynamic injection method was used to generate mice that overexpress SeP mRNA in the liver. Hepatic overexpression of SeP in SeP KO mice lead to a significant increase in LV weight/TL and Lung weight/TL after TAC compared to that in other SeP KO mice. Conclusions These results suggest that cardiac pressure overload induced hepatic expression of SeP and the absence of endogenous SeP attenuated cardiac hypertrophy, dysfunction and fibrosis in response to pressure overload in mice. SeP possibly plays a maladaptive role against progression of heart failure through the liver-heart axis.

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