Humoral factor(s) produced by pressure overload enhance cardiac hypertrophy and natriuretic peptide expression

1997 ◽  
Vol 273 (1) ◽  
pp. H113-H118 ◽  
Author(s):  
T. Iso ◽  
M. Arai ◽  
A. Wada ◽  
K. Kogure ◽  
T. Suzuki ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Natriuretic Peptide ◽  
Aortic Coarctation ◽  
Pressure Overload ◽  
Humoral Factor ◽  
Myosin Isoforms ◽  
Hypertrophic Response ◽  
Cardiac Atrophy ◽  
Transplanted Hearts

Chronic pressure overload is known to increase cardiac mass and expression levels of both atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) mRNAs. Although mechanical stretching of cardiac myocytes could cause these changes, humoral factor(s) secondary to pressure overload may also be involved. To dissociate humoral effects from the effects of mechanical loading on cardiac hypertrophic responses, we examined expression of ANP and BNP at both mRNA and protein levels and proportions of myosin isoforms in transplanted cervical hearts that were mechanically unloaded under conditions with or without hypertension by aortic coarctation. Seven days after transplantation, cardiac atrophy that usually occurs in transplanted hearts without hypertension by coarctation was prevented in the transplanted hearts with hypertension by coarctation. The levels of expression of ANP and BNP mRNAs were increased in the transplanted hearts with relative to those without hypertension by coarctation. The plasma level of angiotensin II was higher in rats with than without hypertension by coarctation. Plasma endothelin-1 levels were not significantly different between the two groups. In addition, levels of expression of ANP and BNP mRNAs were increased in the transplanted hearts without hypertension relative to those in the in situ hearts. The proportion of the V3 myosin isoform was also increased in the transplanted hearts without hypertension relative to the in situ hearts. These results indicate that humoral factor(s) secondary to the pressure overload produced by aortic coarctation enhanced the cardiac hypertrophic response and elevated the levels of mRNAs encoding these embryonic markers. Moreover, our findings regarding ANP and BNP expression in the transplanted hearts provide additional evidence that the fetal genes are reexpressed during the process of cardiac atrophy as well as in cardiac hypertrophy.

Abstract 282: Role of a Disintegrin and Metalloproteinase 15 in Cardiac Hypertrophy and Fibrosis Following Pressure Overload

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Priya Aujla ◽  
Sayantan Jana ◽  
Michael Chute ◽  
Zamaneh Kassiri
Keyword(s):  
Cardiac Hypertrophy ◽  
Cardiac Fibrosis ◽  
Cell Function ◽  
Systolic Function ◽  
Mechanical Strain ◽  
Pressure Overload ◽  
Compensatory Hypertrophy ◽  
Hypertrophic Response ◽  
A Disintegrin And Metalloproteinase

Introduction: Disintegrin and metalloproteinases (ADAMs) are membrane-bound cell surface enzymes that are capable of both proteolytic functions (via the metalloproteinase domain) and adhesive functions (via the disintegrin domain), whereby they can influence cell function and extracellular matrix (ECM) remodelling in the heart. ADAM15 is unique among the ADAMs, as it is also capable of degrading ECM proteins. ADAM12 and ADAM17 have been reported to regulate cardiac hypertrophy, but the role of ADAM15 in cardiac hypertrophy is not known. This study investigates the role of ADAM15 in cardiac hypertrophy and fibrosis following pressure overload. Methods & Results: Genetically modified male ADAM15-deficient ( Adam15 -/- ) and wildtype (WT) mice were subjected to cardiac pressure overload by transverse aortic constriction (TAC). Cardiac function and structural remodelling were assessed using echocardiography at 2-, and 6-wks post-TAC. Hearts were excised at 2-, or 6-wks post-TAC. Adam15 -/- hearts presented greater hypertrophy and decreased cardiac systolic function at 6wks post-TAC, but no difference at 2wks post-TAC compared to WT-TAC mice. Adam15 -/- hearts also showed exacerbated fibrosis at 6wks post-TAC, but not at 2wks post-TAC, compared to WT. Mechanical strain (i.e. pressure overload) triggers two temporally activated pathways leading to an initial compensatory hypertrophy, which can culminate to decompensation and dilated cardiomyopathy. Consistent with the greater hypertrophy, phosphorylation of ERK1/2, JNK1/2/3, and GSK3β was increased in Adam15 -/- mice. The calcineurin-NFAT pathways can mediate pressure overload-induced hypertrophy, but we found that Adam15-deficiency did not impact this pathway. The mechanism responsible for this function of ADAM15 requires further investigation. Conclusion: This study reports a novel cardioprotective function for ADAM15 in pressure overload, where loss of ADAM15 promotes cardiac fibrosis and decompensated cardiac hypertrophy but does not alter the compensated hypertrophic response.

Abstract 191: Phosphodiesterase 9a Modulates Cardiomyocyte Natriuretic Peptide-Stimulated cGMP Pool and Cardiac Hypertrophy

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Dong I Lee ◽  
Takashi Sasaki ◽  
Guangshuo Zhu ◽  
Peter R Rainer ◽  
Manling Zhang ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Gene Silencing ◽  
Natriuretic Peptide ◽  
Stress Responses ◽  
Adult Mouse ◽  
Soluble Guanylate Cyclase ◽  
Pressure Overload ◽  
Cyclic Guanosine Monophosphate ◽  
Negative Control ◽  
Guanosine Monophosphate

Cardiac hypertrophy in response to pathologic stress is a major contributor to heart disease. Many studies have revealed that compartmentalized cyclic guanosine monophosphate (cGMP) regulation by phosphodiesterases (PDEs) can potently modify acute and chronic cardiac stress responses. PDE5a normally regulates cGMP generated from nitric oxide (NO)-stimulated soluble guanylate cyclase (sGC) but not natriuretic peptide (NP)-stimulated cGMP. Its inhibition blunts maladaptive hypertrophy and remodeling. Regulators of NP-cGMP remain uncertain. Here we reveal that PDE9a, a highly cGMP-specific PDE (×100 affinity vs PDE5a) that is expressed predominantly in the brain modulates myocyte cGMP as well, targeting NP-stimulated pools. PDE9a gene expression is observed in rat neonatal cardiac myocytes (RNCM) and adult mouse myocytes. Protein expression was identified in myocytes by immunohistochemistry, using gene silencing models as a negative control. PDE9a expression is upregulated by various hypertrophic stimuli (phenylephrine (PE) or endothelin-1 (ET-1), and observed in myocytes from pressure-overloaded whole myocardium. PDE9a inhibition with a selective antagonist (PF-9613) or gene silencing significantly abrogated PE- or ET-1-dependent upregulation of pathological-hypertrophy fetal genes and NFAT activity in RNCM, and PDE9a inhibition attenuated ET-1-induced hypertrophy in adult mouse myocytes. PF-9613 had no impact in cells lacking PDE9a (from knockout mice) or after gene silencing. Biochemical and cGMP-sensitive fluorescent probe studies shows PDE9a inhibition augments ANP- but not NO-dependent cGMP stimuli in RNCM and adult myocytes. PDE9a knockout (KO) mice were protected against hypertrophy/remodeling after pressure-overload, accompanied by a rise in myocardial cGMP. In PDE9a KO mice also exhibited less fibrosis and reduced expression of fibrotsis-related genes over wild-type mice. Together, these data identify PDE9a as a novel regulator of myocyte cGMP and hypertrophy that impacts a different compartmentalized cGMP pool to that by PDE5a. Our observations may provide a novel therapeutic approach in the treatment of heart failure.

Increased natriuretic peptide receptor A and C gene expression in rats with pressure-overload cardiac hypertrophy

2006 ◽  
Vol 290 (4) ◽  
pp. H1635-H1641 ◽  
Author(s):  
Tue E. H. Christoffersen ◽  
Mark Aplin ◽  
Claes C. Strom ◽  
Soren P. Sheikh ◽  
Ole Skott ◽  
...  
Keyword(s):  
Gene Expression ◽  
Left Ventricle ◽  
Cardiac Hypertrophy ◽  
Natriuretic Peptide ◽  
Pressure Overload ◽  
Renin Angiotensin System ◽  
Left Ventricular ◽  
Natriuretic Peptide Receptor ◽  
Angiotensin System ◽  
Peptide Receptor

Both atrial (ANP) and brain (BNP) natriuretic peptide affect development of cardiac hypertrophy and fibrosis via binding to natriuretic peptide receptor (NPR)-A in the heart. A putative clearance receptor, NPR-C, is believed to regulate cardiac levels of ANP and BNP. The renin-angiotensin system also affects cardiac hypertrophy and fibrosis. In this study we examined the expression of genes for the NPRs in rats with pressure-overload cardiac hypertrophy. The ANG II type 1 receptor was blocked with losartan (10 mg·kg−1·day−1) to investigate a possible role of the renin-angiotensin system in regulation of natriuretic peptide and NPR gene expression. The ascending aorta was banded in 84 rats during Hypnorm/Dormicum-isoflurane anesthesia; after 4 wk the rats were randomized to treatment with losartan or placebo. The left ventricle of the heart was removed 1, 2, or 4 wk later. Aortic banding increased left ventricular expression of NPR-A and NPR-C mRNA by 110% ( P < 0.001) and 520% ( P < 0.01), respectively, after 8 wk; as expected, it also increased the expression of ANP and BNP mRNAs. Losartan induced a slight reduction of left ventricular weight but did not affect the expression of mRNAs for the natriuretic peptides or their receptors. Although increased gene expression does not necessarily convey a higher concentration of the protein, the data suggest that pressure overload is accompanied by upregulation of not only ANP and BNP but also their receptors NPR-A and NPR-C in the left ventricle.

Pressure-overload hypertrophy is unabated in mice devoid of AT1A receptors

1998 ◽  
Vol 274 (3) ◽  
pp. H868-H873 ◽  
Author(s):  
Masayoshi Hamawaki ◽  
Thomas M. Coffman ◽  
Andrew Lashus ◽  
Masaaki Koide ◽  
Michael R. Zile ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Knockout Mice ◽  
Weight Ratio ◽  
Pressure Overload ◽  
Renin Angiotensin System ◽  
Left Ventricular ◽  
Wild Type ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Hypertrophic Response

Mechanisms controlling cardiac growth are under intense investigation. Among these, the renin-angiotensin system has received great interest. In the current study, we tested the hypothesis that the renin-angiotensin system was not an obligate factor in cardiac hypertrophy. We examined the left ventricular hypertrophic response to a pressure overload in mice devoid of the AT1A receptor, the putative major effector of the growth response of the renin-angiotensin system. Aortic banding produced similar transband gradients in wild-type and AT1A knockout mice. The left ventricular mass-to-body weight ratio increased from 3.44 ± 0.08 to 5.62 ± 0.25 in wild-type ascending aortic-banded mice. The response in the knockout mice was not different (from 2.97 ± 0.13 to 5.24 ± 0.37). We conclude that the magnitude of cardiac hypertrophy is not affected by the absence of the AT1A receptor and its signaling pathway and that this component of the renin-angiotensin system is not necessary in cardiac hypertrophy.

Endothelin-1 and its binding sites are upregulated in pressure overload cardiac hypertrophy

1995 ◽  
Vol 268 (5) ◽  
pp. H2084-H2091 ◽  
Author(s):  
M. Arai ◽  
A. Yoguchi ◽  
T. Iso ◽  
T. Takahashi ◽  
S. Imai ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Binding Sites ◽  
Pressure Overload ◽  
Sham Operation ◽  
Endothelin 1 ◽  
Important Relationship ◽  
Mrna Hybridization ◽  
In Situ Mrna Hybridization

The purpose of this study was to determine whether endothelin and endothelin receptors play an important role in the development of cardiac hypertrophy due to pressure overload in vivo. Cardiac hypertrophy was produced by placing a constricting clip around the suprarenal abdominal aorta of rats. Hemodynamic parameters and plasma and ventricular concentrations of endothelin-1 (ET-1) were measured in control unoperated rats, and 30 min, 2 and 6 h, and 1 and 8 days after operation in pressure overload rats and sham-operated rats. The density and dissociation constant of ET-1 binding sites were also measured in control rats and 1 and 8 days after pressure overload and sham operation. Additionally, in situ mRNA hybridization for preproendothelin-1 (preproET-1) mRNA was performed to determine which cells were responsible for increased ET-1 levels. Ventricular ET-1 levels increased markedly on day 8 of pressure overload, whereas plasma ET-1 levels increased transiently only 30 min after operation, quickly returning to control level. In addition, ventricular ET-1 levels on day 8 showed a significant positive correlation with the degree of cardiac hypertrophy. In situ mRNA hybridization revealed that cardiac myocytes expressed preproET-1 mRNA in hypertrophied hearts in vivo. In accord with the elevation of ventricular ET-1 levels, the density of ET-1 binding sites was increased significantly, without affecting their binding affinity, on day 8 of pressure overload. These data are compatible with the hypothesis that increases in locally produced ET-1 and the density of ET-1 binding sites have an important relationship with the development of cardiac hypertrophy in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)

In situ mitochondrial function in volume overload- and pressure overload-induced cardiac hypertrophy in rats

1995 ◽  
Vol 90 (4) ◽  
pp. 305-313 ◽  
Author(s):  
Mong Hung Bui ◽  
R. Janati-Idrissi ◽  
B. Besson ◽  
M. Laplace
Keyword(s):  
Cardiac Hypertrophy ◽  
Mitochondrial Function ◽  
Pressure Overload ◽  
Volume Overload

Abstract 1831: Phosphodiesterase-5 Inhibition Prevents Cardiac Hypertrophy, Independently of the Calcineurin Pathway

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Steven Hsu ◽  
Takahiro Nagayama ◽  
Norimichi Koitabashi ◽  
Liye Zhou ◽  
Manling Zhang ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Glycogen Synthase ◽  
Pressure Overload ◽  
Hypertrophic Response ◽  
Calmodulin Kinase ◽  
Residual Response ◽  
Systolic And Diastolic Function ◽  
Phosphodiesterase 5 ◽  
Tibia Length

Cyclic GMP and its downstream kinase protein kinase G (PKG) negatively regulate cardiac hypertrophy. To date the only documented target of this cascade is the serine-threonine phosphatase calcineurin (Cn), whose activation is central to the development of pathologic cardiac hypertrophy. Recently, we reported that phosphodiesterase 5 (PDE5) inhibition (sildenafil, SIL) activates myocardial PKG and prevents pressure-overload induced hypertrophy by suppressing multiple cascades including Cn. To test the centrality of Cn signaling to the in vivo anti-hypertrophic effects of SIL, we subjected mice deficient in the Cn-A β subunit (CnA β −/− ) to severe trans-aortic constriction (TAC) with or without SIL (100mg/kg/day, p.o.) for 3-wks. TAC induced less hypertrophy that was more concentric in CnA β −/− vs WT-controls (50% vs 100% increase in heart mass/tibia length, p<0.03). SIL completely blocked the hypertrophic response and fully normalized fetal gene re-expression (e.g ANP, BNP and β MHC) in CnA β −/− TAC hearts, while it inhibited LVH by 60% and suppressed ANP and β MHC in WT-TAC hearts. SIL improved cardiac systolic and diastolic function (pressure-volume analysis) in CnA β −/− TAC hearts much as in WT-TAC hearts. In CnA β −/− TAC hearts, phosphorylated calcium calmodulin kinase II (CaMK II) increased 10-fold versus only a 2-fold rise in WT-TAC, whereas Akt and glycogen synthase kinase 3 β (GSK3 β ) activation were comparable between groups. Extracellular response kinase (ERK) 1/2 was activated with TAC in WT hearts only. Importantly, SIL stimulated myocardial PKG and markedly inhibited the activation of CaMKII, Akt and GSK3 β similarly in both groups exposed to TAC. Thus, Cn is not required for the anti-hypertrophic effects of SIL. Though TAC-induced hypertrophy is less in CnA β −/− mice, SIL remains effective in suppressing the residual response by targeting alternative cascades such as CaMK II. These findings suggest that SIL acts either on multiple pathways concurrently, or at a node proximal to these pathways likely at or near the sarcolemmal membrane.

Cathepsin B deficiency attenuates cardiac remodeling in response to pressure overload via TNF-α/ASK1/JNK pathway

2015 ◽  
Vol 308 (9) ◽  
pp. H1143-H1154 ◽  
Author(s):  
Qing-Qing Wu ◽  
Man Xu ◽  
Yuan Yuan ◽  
Fang-Fang Li ◽  
Zheng Yang ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Cardiac Remodeling ◽  
Cathepsin B ◽  
Cathepsin L ◽  
Pressure Overload ◽  
Jnk Pathway ◽  
Hypertrophic Response ◽  
Tnf Α

Cathepsin B (CTSB), a member of the lysosomal cathepsin family that is expressed in both murine and human hearts, was previously shown to participate in apoptosis, autophagy, and the progression of certain types of cancers. Recently, CTSB has been linked to myocardial infarction. Given that cathepsin L, another member of the lysosomal cathepsin family, ameliorates pathological cardiac hypertrophy, we hypothesized that CTSB plays a role in pressure overload-induced cardiac remodeling. Here we report that CTSB was upregulated in cardiomyocytes in response to hypertrophic stimuli both in vivo and in vitro. Moreover, knockout of CTSB attenuated pressure overload-induced cardiac hypertrophy, fibrosis, dysfunction, and apoptosis. Furthermore, the aortic banding-induced activation of TNF-α, apoptosis signal-regulating kinase 1 (ASK1), c-Jun NH2-terminal kinases (JNK), c-Jun, and release of cytochrome c was blunted by CTSB deficiency, which was further confirmed in in vitro studies induced by angiotensin II. In cardiomyocytes pretreatment with SP600125, a JNK inhibitor, suppressed the cardiomyocytes hypertrophy by inhibiting the ASK1/JNK pathway. Altogether, these data indicate that the CTSB protein functions as a necessary modulator of hypertrophic response by regulating TNF-α/ASK1/JNK signaling pathway involved in cardiac remodeling.

scholarly journals The immunoproteasome catalytic β5i subunit regulates cardiac hypertrophy by targeting the autophagy protein ATG5 for degradation

2019 ◽  
Vol 5 (5) ◽  
pp. eaau0495 ◽  
Author(s):  
Xin Xie ◽  
Hai-Lian Bi ◽  
Song Lai ◽  
Yun-Long Zhang ◽  
Nan Li ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Inflammatory Diseases ◽  
Pressure Overload ◽  
Cardiomyocyte Hypertrophy ◽  
Ang Ii ◽  
Adequate Treatment ◽  
Hypertrophic Response ◽  
Pathological Cardiac Hypertrophy ◽  
Mediated Reduction ◽  
Expression And Activity

Pathological cardiac hypertrophy eventually leads to heart failure without adequate treatment. The immunoproteasome is an inducible form of the proteasome that is intimately involved in inflammatory diseases. Here, we found that the expression and activity of immunoproteasome catalytic subunit β5i were significantly up-regulated in angiotensin II (Ang II)–treated cardiomyocytes and in the hypertrophic hearts. Knockout of β5i in cardiomyocytes and mice markedly attenuated the hypertrophic response, and this effect was aggravated by β5i overexpression in cardiomyocytes and transgenic mice. Mechanistically, β5i interacted with and promoted ATG5 degradation thereby leading to inhibition of autophagy and cardiac hypertrophy. Further, knockdown of ATG5 or inhibition of autophagy reversed the β5i knockout-mediated reduction of cardiomyocyte hypertrophy induced by Ang II or pressure overload. Together, this study identifies a novel role for β5i in the regulation of cardiac hypertrophy. The inhibition of β5i activity may provide a new therapeutic approach for hypertrophic diseases.

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