scholarly journals Pregnancy mitigates cardiac pathology in a mouse model of left ventricular pressure overload

2016 ◽  
Vol 311 (3) ◽  
pp. H807-H814 ◽  
Author(s):  
Hong Xu ◽  
Elza D. van Deel ◽  
Mark R. Johnson ◽  
Petra Opić ◽  
Bronwen R. Herbert ◽  
...  
Keyword(s):  
Gene Expression ◽  
Heart Disease ◽  
Interstitial Fibrosis ◽  
Experimental Studies ◽  
Pressure Overload ◽  
Left Ventricular Pressure ◽  
Capillary Density ◽  
Left Ventricular ◽  
Lv Function ◽  
Lung Weight

In Western countries heart disease is the leading cause of maternal death during pregnancy. The effect of pregnancy on the heart is difficult to study in patients with preexisting heart disease. Since experimental studies are scarce, we investigated the effect of pressure overload, produced by transverse aortic constriction (TAC) in mice, on the ability to conceive, pregnancy outcome, and maternal cardiac structure and function. Four weeks of TAC produced left ventricular (LV) hypertrophy and dysfunction with marked interstitial fibrosis, decreased capillary density, and induced pathological cardiac gene expression. Pregnancy increased relative LV and right ventricular weight without affecting the deterioration of LV function following TAC. Surprisingly, the TAC-induced increase in relative heart and lung weight was mitigated by pregnancy, which was accompanied by a trend towards normalization of capillary density and natriuretic peptide type A expression. Additionally, the combination of pregnancy and TAC increased the cardiac phosphorylation of c-Jun, and STAT1, but reduced phosphoinositide 3-kinase phosphorylation. Finally, TAC did not significantly affect conception rate, pregnancy duration, uterus size, litter size, and pup weight. In conclusion, we found that, rather than exacerbating the changes associated with cardiac pressure overload, pregnancy actually attenuated pathological LV remodeling and mitigated pulmonary congestion, and pathological gene expression produced by TAC, suggesting a positive effect of pregnancy on the pressure-overloaded heart.

scholarly journals NADPH oxidase-4 promotes eccentric cardiac hypertrophy in response to volume overload

2019 ◽  
Author(s):  
Moritz Schnelle ◽  
Iain Sawyer ◽  
Narayana Anilkumar ◽  
Belal A Mohamed ◽  
Daniel A Richards ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Cardiac Hypertrophy ◽  
Interstitial Fibrosis ◽  
Pressure Overload ◽  
Volume Overload ◽  
Capillary Density ◽  
Left Ventricular ◽  
Cardiac Cells ◽  
Cross Sectional ◽  
Nadph Oxidase 4

Abstract Aims Chronic pressure or volume overload induce concentric vs. eccentric left ventricular (LV) remodelling, respectively. Previous studies suggest that distinct signalling pathways are involved in these responses. NADPH oxidase-4 (Nox4) is a reactive oxygen species-generating enzyme that can limit detrimental cardiac remodelling in response to pressure overload. This study aimed to assess its role in volume overload-induced remodelling. Methods and results We compared the responses to creation of an aortocaval fistula (Shunt) to induce volume overload in Nox4-null mice (Nox4−/−) vs. wild-type (WT) littermates. Induction of Shunt resulted in a significant increase in cardiac Nox4 mRNA and protein levels in WT mice as compared to Sham controls. Nox4−/− mice developed less eccentric LV remodelling than WT mice (echocardiographic relative wall thickness: 0.30 vs. 0.27, P < 0.05), with less LV hypertrophy at organ level (increase in LV weight/tibia length ratio of 25% vs. 43%, P < 0.01) and cellular level (cardiomyocyte cross-sectional area: 323 µm2 vs. 379 μm2, P < 0.01). LV ejection fraction, foetal gene expression, interstitial fibrosis, myocardial capillary density, and levels of myocyte apoptosis after Shunt were similar in the two genotypes. Myocardial phospho-Akt levels were increased after induction of Shunt in WT mice, whereas levels decreased in Nox4−/− mice (+29% vs. −21%, P < 0.05), associated with a higher level of phosphorylation of the S6 ribosomal protein (S6) and the eIF4E-binding protein 1 (4E-BP1) in WT compared to Nox4−/− mice. We identified that Akt activation in cardiac cells is augmented by Nox4 via a Src kinase-dependent inactivation of protein phosphatase 2A. Conclusion Endogenous Nox4 is required for the full development of eccentric cardiac hypertrophy and remodelling during chronic volume overload. Nox4-dependent activation of Akt and its downstream targets S6 and 4E-BP1 may be involved in this effect.

scholarly journals Regression of pressure overload-induced left ventricular hypertrophy in mice

2005 ◽  
Vol 288 (6) ◽  
pp. H2702-H2707 ◽  
Author(s):  
Xiao-Ming Gao ◽  
Helen Kiriazis ◽  
Xiao-Lei Moore ◽  
Xin-Heng Feng ◽  
Karen Sheppard ◽  
...  
Keyword(s):  
Gene Expression ◽  
Time Course ◽  
Interstitial Fibrosis ◽  
Gene Expression Pattern ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Matrix Metalloproteinase 2 ◽  
Aortic Banding ◽  
Genetic Components ◽  
Collagen Iii

As a prelude to investigating the mechanism of regression of pressure overload-induced left ventricular (LV) hypertrophy (LVH), we studied the time course for the development and subsequent regression of LVH as well as accompanying alterations in cardiac function, histology, and gene expression. Mice were subjected to aortic banding for 4 or 8 wk to establish LVH, and regression was initiated by release of aortic banding for 6 wk. Progressive increase in LV mass and gradual chamber dilatation and dysfunction occurred after aortic banding. LVH was also associated with myocyte enlargement, interstitial fibrosis, and enhanced expression of atrial natriuretic peptide, collagen I, collagen III, and matrix metalloproteinase-2 but suppressed expression of α-myosin heavy chain and sarcoplasmic reticulum Ca2+-ATPase. Aortic debanding completely or partially reversed LVH, chamber dilatation and dysfunction, myocyte size, interstitial fibrosis, and gene expression pattern, each with a distinct time course. The extent of LVH regression was dependent on the duration of pressure overload, evidenced by the fact that restoration of LV structure and function was complete in animals subjected to 4 wk of aortic banding but incomplete in animals subjected to 8 wk of aortic banding. In conclusion, LVH regression comprises a variety of morphological, functional, and genetic components that show distinct time courses. A longer period of pressure overload is associated with a slower rate of LVH regression.

Minoxidil accelerates heart failure development in rats with ascending aortic constriction

1998 ◽  
Vol 76 (6) ◽  
pp. 613-620 ◽  
Author(s):  
Marian Turcani ◽  
Ruthard Jacob
Keyword(s):  
Heart Failure ◽  
Myocardial Contractility ◽  
Pressure Overload ◽  
Volume Overload ◽  
Left Ventricular Pressure ◽  
Left Ventricular ◽  
Aortic Constriction ◽  
Lung Weight ◽  
Eccentric Hypertrophy ◽  
Hemodynamic Overload

To test the ability of the heart to express characteristic geometric features of concentric and eccentric hypertrophy concurrently, constriction of the ascending aorta was performed in 4-week-old rats. Simultaneously, these rats were treated with an arteriolar dilator minoxidil. An examination 6 weeks after induction of the hemodynamic overload revealed no signs of congestion in systemic or pulmonary circulation in rats with aortic constriction or minoxidil-treated sham-operated rats. The magnitude of hemodynamic overload caused by aortic constriction or minoxidil treatment could be considered as equivalent, because the same enlargement of left ventricular pressure-volume area was necessary to compensate for either pressure or volume overload. Myocardial contractility decreased in rats with aortic constriction, and the compensation was achieved wholly by the marked concentric hypertrophy. Volume overload in minoxidil-treated rats was compensated partially by the eccentric hypertrophy and partially by the increased myocardial contractility. In contrast, increased lung weight and pleural effusion were found in all minoxidil-treated rats with aortic constriction. Unfavorable changes in left ventricular mass and geometry, relatively high chamber stiffness, and depressed ventricular and myocardial function were responsible for the massive pulmonary congestion.Key words: cardiac hypertrophy, heart failure, pressure overload, volume overload, minoxidil.

scholarly journals IL-18 induction of osteopontin mediates cardiac fibrosis and diastolic dysfunction in mice

2009 ◽  
Vol 297 (1) ◽  
pp. H76-H85 ◽  
Author(s):  
Qianli Yu ◽  
Randy Vazquez ◽  
Elham Vali Khojeini ◽  
Chirag Patel ◽  
Raj Venkataramani ◽  
...  
Keyword(s):  
Diastolic Dysfunction ◽  
Cardiac Fibrosis ◽  
Interstitial Fibrosis ◽  
Cardiac Fibroblasts ◽  
Pressure Overload ◽  
Volume Overload ◽  
Left Ventricular Pressure ◽  
Neutralizing Antibody ◽  
Left Ventricular ◽  
Fibrotic Process

Osteopontin (OPN), a key component of the extracellular matrix, is associated with the fibrotic process during tissue remodeling. OPN and the cytokine interleukin (IL)-18 have been shown to be overexpressed in an array of human cardiac pathologies. In the present study, we determined the role of IL-18 in the regulation of cardiac OPN expression and the subsequent interstitial fibrosis and diastolic dysfunction. We demonstrated parallel increases in IL-18, OPN expression, and interstitial fibrosis in murine models of left ventricular pressure and volume overload. Exogenous recombinant (r)IL-18 administered for 2 wk increased cardiac OPN expression, interstitial fibrosis, and diastolic dysfunction. Stimulation of the T helper (Th)1 lymphocyte phenotype with a selective toll-like receptor (TLR)9 agonist induced cardiac IL-18 and OPN expression, which was associated with increased cardiac fibrillar collagen concentrations and interstitial fibrosis resulting in diastolic dysfunction. rIL-18 induced OPN expression and protein levels in primary of cardiac fibroblast cultures. Conditioned media from TLR9-stimulated T lymphocyte cultures induced IL-18 and OPN expression in cardiac fibroblasts, while blockade of the IL-18 receptor with a neutralizing antibody abolished the increase in OPN expression. Furthermore, a mutation in the transcriptional factor interferon regulatory factor (IRF)1 or IRF1 small interfering RNA (siRNA) resulted in the decreased expression of IL-18 and OPN in cardiac fibroblasts. With pressure overload, IRF1-mutant mice showed downregulation of IL-18 and OPN expression in cardiac tissue, reduced cardiac fibrotic development, and increased left ventricular function compared with wild type. These results provide direct evidence that the induction of IL-18 regulates OPN-mediated cardiac fibrosis and diastolic dysfunction.

Sepiapterin prevents left ventricular hypertrophy and dilatory remodeling induced by pressure overload in rats

2015 ◽  
Vol 309 (10) ◽  
pp. H1782-H1791 ◽  
Author(s):  
Kei Yoshioka ◽  
Hajime Otani ◽  
Takayuki Shimazu ◽  
Masanori Fujita ◽  
Toshiji Iwasaka ◽  
...  
Keyword(s):  
Ventricular Hypertrophy ◽  
Interstitial Fibrosis ◽  
Pressure Overload ◽  
Capillary Density ◽  
Left Ventricular ◽  
Cardiomyocyte Hypertrophy ◽  
Salvage Pathway ◽  
Aortic Constriction ◽  
Beneficial Effects ◽  
Lv Remodeling

Uncoupling of nitric oxide (NO) synthase (NOS) has been implicated in left ventricular (LV) hypertrophy (LVH) and dilatory remodeling induced by pressure overload. We investigated whether administration of sepiapterin, a substrate of the salvage pathway of tetrahydrobiopterin synthesis, prevents LVH and dilatory LV remodeling by inhibiting NOS uncoupling and increasing bioavailable NO. Pressure overload was induced in rats by transverse aortic constriction (TAC). Concentric LVH developed during 8 wk after TAC, and dilatory LV remodeling and dysfunction developed between 8 and 16 wk after TAC associated with a decrease in capillary density. Oral administration of sepiapterin or the superoxide/peroxynitrite scavenger N-(2-mercaptopropionyl)-glycine for 8 wk after TAC inhibited oxidative stress, but only sepiapterin increased bioavailable NO and inhibited cardiomyocyte hypertrophy associated with a further increase in capillary density. When sepiapterin was administered between 8 and 16 wk after TAC, cardiomyocyte hypertrophy was regressed and capillary density was restored. This was associated with the inhibition of interstitial fibrosis and dilatory LV remodeling. N-nitro-l-arginine methyl ester abrogated all the beneficial effects of sepiapterin in rats with TAC. These results suggest that sepiapterin prevents concentric LVH and dilatory remodeling after TAC primarily by increasing the bioavailability of NO.

scholarly journals mTOR attenuates the inflammatory response in cardiomyocytes and prevents cardiac dysfunction in pathological hypertrophy

2010 ◽  
Vol 299 (6) ◽  
pp. C1256-C1266 ◽  
Author(s):  
Xiaoxiao Song ◽  
Yoichiro Kusakari ◽  
Chun-Yang Xiao ◽  
Stuart D. Kinsella ◽  
Michael A. Rosenberg ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Cardiac Dysfunction ◽  
Interstitial Fibrosis ◽  
Mammalian Target Of Rapamycin ◽  
Pressure Overload ◽  
Left Ventricular Pressure ◽  
Mtor Inhibitors ◽  
Left Ventricular ◽  
Adverse Outcomes ◽  
Pathological Hypertrophy

Previous studies have suggested that inhibition of the mammalian target of rapamycin (mTOR) by rapamycin suppresses myocardial hypertrophy. However, the role of mTOR in the progression of cardiac dysfunction in pathological hypertrophy has not been fully defined. Interestingly, recent reports indicate that the inflammatory response, which plays an important role in the development of heart failure, is enhanced by rapamycin under certain conditions. Our aim in this study was to determine the influence of mTOR on pathological hypertrophy and to assess whether cardiac mTOR regulates the inflammatory response. We generated transgenic mice with cardiac-specific overexpression of wild-type mTOR (mTOR-Tg). mTOR-Tg mice were protected against cardiac dysfunction following left ventricular pressure overload induced by transverse aortic constriction (TAC) ( P < 0.01) and had significantly less interstitial fibrosis compared with littermate controls (WT) at 4 wk post-TAC ( P < 0.01). In contrast, TAC caused cardiac dysfunction in WT. At 1 wk post-TAC, the proinflammatory cytokines interleukin (IL)-1β and IL-6 were significantly increased in WT mice but not in mTOR-Tg mice. To further characterize the effects of mTOR activation, we exposed HL-1 cardiomyocytes transfected with mTOR to lipopolysaccharide (LPS). mTOR overexpression suppressed LPS-induced secretion of IL-6 ( P < 0.001), and the mTOR inhibitors rapamycin and PP242 abolished this inhibitory effect of mTOR. In addition, mTOR overexpression reduced NF-κB-regulated transcription in HL-1 cells. These data suggest that mTOR mitigates adverse outcomes of pressure overload and that this cardioprotective effect of mTOR is mediated by regulation of the inflammatory reaction.

Abstract 5907: Development of Left Ventricular Dysfunction During Progression of Infant Right Ventricular Hypertrophy

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Kazuo Kitahori ◽  
Huamei He ◽  
Douglas B Cowan ◽  
Ingeborg Friehs ◽  
Pedro J Nido ◽  
...  
Keyword(s):  
Right Ventricular ◽  
Ex Vivo ◽  
Late Complication ◽  
Pressure Overload ◽  
Capillary Density ◽  
Left Ventricular ◽  
Lv Function ◽  
Lv Dysfunction ◽  
Lv Remodeling ◽  
Point Total

Background: Progressive left ventricular (LV) dysfunction can be a major late complication in patients with chronic right ventricular (RV) pressure overload (e.g. tetralogy of Fallot). The mechanisms remains unclear. We therefore examined LV function (serial echocardiography and ex vivo Langendorff) and histology in a model of infant pressure-load RV hypertrophy (RVH). Methods and Results: Ten-day-old rabbits (N=6 per time point, total =48) underwent pulmonary artery banding (PAB), were sacrificed at 2–8 weeks after PAB, and compared to age-matched sham controls. Both RV and LV performance (myocardial performance index, MPI; fractional area change, FAC), measured by echocardiography, decreased during the progression of RVH (Table ). In addition, RVH caused significant septal displacement, reduced septal contractility, and decreased LV end-systolic (LVDs) and diastolic (LVDd) dimensions. Significant septal and LV free wall apoptosis (myocyte-specific TUNEL and activated caspase-3), fibrosis (Masson’s Trichrome), and reduced capillary density (CD31 immunostaining) occurred in the left ventricles of the PAB group after 6 – 8 wks (all p<0.05). Conclusion: This study for the first time shows that pressure overload resulting in RVH causes LV dysfunction by both mechanical and molecular effects upon the septum and LV myocardium. In particular, the development of RVH is associated with septal and LV apoptosis, pathologic LV remodeling, and reduced LV capillary density. Potential mediators and mechanisms (e.g. paracrine vs. circulating stimuli) merit further investigation LV performance during the progression of RVH

Abstract 5394: H11 Kinase/Hsp22, A Novel Mechanism in the Transition to Heart Failure

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Hongyu Qiu ◽  
Chull Hong ◽  
Shumin Gao ◽  
Dorothy E Vatner ◽  
Stephen F Vatner ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Diastolic Pressure ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Lv Function ◽  
Area At Risk ◽  
Lung Weight ◽  
Tibial Length ◽  
Lv Ejection Fraction

H11 kinase/Hsp22 (H11K), a heat shock protein expressed mainly in the heart, is up-regulated upon pressure overload in animal models and in patients. Cardiac-specific over-expression of H11K in a transgenic model induces cardiac hypertrophy with normal function and cardioprotection against lethal ischemia. We tested the hypothesis that H11K deletion would accelerate the transition into heart failure (HF) following chronic pressure overload. An H11K knockout (KO) mouse was generated, which survives after birth with normal Mendelian distribution. In basal conditions (4/group), no differences were found between KO and wild type (WT) in terms of left ventricular (LV) mass (LV/tibial length: 4.6±0.3 vs 4.1±0.1, NS) or LV ejection fraction (69±3% vs 70±1%, NS). After two weeks aortic banding the KO mice, compared to WT, showed a slightly greater mass (LV/tibial length: 8.2±0.3 vs 7.0±0.4, P<0.05), impaired LV function (LV ejection fraction: 45±3% vs 62±5%, P<0.05), and signs of HF (lung weight/TL: 16.2±3 vs 7.7±0.4, P<0.05; LV end-diastolic pressure: 22±4 mmHg vs 7±4 mmHg, P<0.05). To test whether H11K participates in cardiac cell survival, both WT and KO mice were submitted to 30 min no-flow ischemia of the left anterior descending artery followed by 24 hours reperfusion and staining for the area-at-risk (AAR) and infarct size (IS). Whereas AAR was comparable between groups, the IS/AAR was more than doubled (P<0.01, n=3/group) in KO (61±2.8%) compared to WT (26±2.8%). Therefore, H11K deletion does not affect basal cardiac function but it precipitates the transition into HF following pressure overload, potentially by loss of H11K cardioprotective action. This research has received full or partial funding support from the American Heart Association, AHA National Center.

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