Abstract 83: Autophagy Protects the Heart Against Pressure Overload Induced Heart Failure

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Akihiro Shirakabe ◽  
Yoshiyuki Ikeda ◽  
Toshiro Saito ◽  
Peiyong Zhai ◽  
Junichi Sadoshima
Keyword(s):  
Heart Failure ◽  
Cardiac Dysfunction ◽  
Sham Group ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Autophagic Flux ◽  
Multiple Time ◽  
Double Positive ◽  
Lung Weight ◽  
Multiple Time Points

Autophagy is an important mechanism for the degradation of cytosolic proteins and organelles. We investigated how autophagy is regulated in the heart in response to pressure overload (PO). Mice were subjected to transverse aortic constriction (TAC) at multiple time points between 1 hours and 30 days. Left ventricular (LV) weight/tibial length (TL) was significantly elevated at Day 5 (6.21 ± 0.10 vs 4.59 ± 0.10, p<0.05) and thereafter. Ejection fraction (EF) was maintained at Day 7 (82.1±3.4 vs 78.4±3.2%), but gradually decreased thereafter (at Day 30; 51.0±4.5, p<0.05). The level of LC3II was rapidly increased and peaked at 3 hour (2.4 fold , p<0.05), returned to normal by 24 hours, and then significantly decreased at Day 5 (-40.0%, p<0.05) and thereafter. Autophagic flux was evaluated with tandem fluorescent LC3. At 6 hours, both GFP/RFP double positive (yellow) dots and RFP dots were significantly increased in the TAC group compared to the sham group with or without chloroquine (CQ) (yellow 12±2 vs 4±0 CQ(-), 23±3 vs 9±1 CQ(+); RFP 13±2 vs 5±1 CQ(-), 19±1 vs 13±1 CQ(+)). On the other hand, both yellow and RFP dots were significantly decreased at Day7 and thereafter in the TAC group compared to the sham group with or without CQ. These data suggest that autophagic flux is activated transiently after TAC, but is inactivated after Day 5. To examine the functional significance of autophagy during PO, beclin1 heterozygous KO ( beclin1 -hetKO) mice, atg7 cardiac specific KO (Atg7-CKO) mice, and cardiac-specific U6-shRNA beclin1 (U6shRNA beclin1 ) mice were subjected to TAC. At Day 7 or 14, decreases in EF (60.7 ± 4.8%, 53.8 ± 2.1% and 46.7 ± 5.9%, p<0.05) and increases in lung weight/TL (8.43 ± 0.87, 11.04 ± 4.16 and 18.76 ± 3.77, p<0.05) were exacerbated in beclin1 -hetKO, atg7 -CKO and U6shRNA beclin1 mice compared to in control mice. These results suggest that PO inhibits autophagy after Day5, which coincides with the development of cardiac dysfunction. Since heart failure is exacerbated by further suppression of autophagy, autophagy during PO protects the heart from cardiac dysfunction.

Abstract 17583: Autophagy Protects the Heart Against Pressure Overload Induced Heart Failure

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Akihiro Shirakabe ◽  
Yoshiyuki Ikeda ◽  
Peiyong Zai ◽  
Toshiro Saito ◽  
Junichi Sadoshima
Keyword(s):  
Heart Failure ◽  
Cardiac Dysfunction ◽  
Sham Group ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Autophagic Flux ◽  
Aortic Constriction ◽  
Double Positive ◽  
Lung Weight ◽  
Transient Activation

Autophagy is an important mechanism for the degradation of cytosolic proteins and organelles. We investigated how autophagy is regulated in the heart in response to pressure overload (PO). Mice were subjected to transverse aortic constriction (TAC) for multiple durations ranging from 1 hour to 30 days. Left ventricular (LV) weight/tibial length (TL) was significantly elevated at Day 5 (6.21 ± 0.10 vs 4.59 ± 0.10, p<0.05) and thereafter. Ejection fraction (EF) was maintained at Day 7 (82.1±3.4 vs 78.4±3.2%), but gradually decreased thereafter (at Day 30, 51.0±4.5, p<0.05). The level of LC3II increased rapidly, peaking at 3 hours (2.4 fold, p<0.05), returned to normal by 24 hours, and then was significantly decreased at Day 5 (-40.0%, p<0.05) and thereafter. Autophagic flux was evaluated with tandem fluorescent LC3. At 6 hours, both GFP/RFP double positive (yellow) dots and RFP dots were significantly increased in the TAC group compared to the sham group, with or without chloroquine (CQ) (yellow 12±2 vs 4±0 CQ(-), 23±3 vs 9±1 CQ(+); RFP 13±2 vs 5±1 CQ(-), 19±1 vs 13±1 CQ(+)). However, both yellow and RFP dots were significantly decreased at Day 7 and thereafter in the TAC group compared to the sham group, with or without CQ. These data suggest that autophagic flux is activated only transiently after TAC, but is inactivated after Day 5. To examine the functional significance of autophagy during PO, beclin1 heterozygous knockout (beclin1-hetKO) mice, atg7 cardiac-specific knockout (Atg7-CKO) mice, and cardiac-specific U6-shRNA beclin1 (U6shRNAbeclin1) mice were subjected to TAC. At Day 7 and 14 of TAC, decreases in EF (60.7 ± 4.8%, 53.8 ± 2.1% and 46.7 ± 5.9%, p<0.05) and increases in lung weight/TL (8.43 ± 0.87, 11.04 ± 4.16 and 18.76 ± 3.77, p<0.05) were exacerbated in beclin1-hetKO, atg7-CKO and U6shRNAbeclin1 mice compared to in control mice. These results suggest that, after transient activation during the initial 24 hours, PO inhibits autophagy below control levels after Day 5, which coincides with the development of cardiac dysfunction. Since heart failure is exacerbated by further suppression of autophagy, autophagy during PO protects the heart from cardiac dysfunction and PO-induced downregulation of autophagy exacerbates heart failure.

Abstract 13469: Drp1 Accumulates in Mitochondria and Plays a Protective Role in the Heart in Response to Pressure Overload

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Akihiro Shirakabe ◽  
Yoshiyuki Ikeda ◽  
Peiyong Zai ◽  
Junichi Sadoshima
Keyword(s):  
Diastolic Pressure ◽  
Pressure Overload ◽  
Protective Role ◽  
Left Ventricular ◽  
Multiple Time ◽  
Lung Weight ◽  
Knock Out ◽  
Multiple Time Points ◽  
Increased Activity ◽  
Adaptive Role

Dynamin-related protein 1 (Drp1) plays an essential role in maintaining the quality control of mitochondria through mitochondrial (Mt) fission and mitophagy. We investigated how Mt function, autophagy and Drp1 are regulated in the heart during pressure overload (PO) and whether endogenous Drp1 plays an important role in regulating cardiac function. Mice were subjected to transverse aortic constriction (TAC) at multiple time points between 6 hours and 30 days. Left ventricular (LV) weight/tibial length (LVW/TL) was significantly elevated at Day 7 (TAC vs sham; 5.92 ± 0.27 vs 4.22 ± 0.12, p<0.05). Ejection fraction (EF) was maintained at Day 7, but gradually decreased thereafter (at 30 days; 65±9 vs 83±9 %, p<0.05). LC3-II was decreased (-45.7%, p<0.05) while p62 accumulated (1.17 fold, p<0.05) significantly at Day 7. Both Mt ATP content (-65.6%, p<0.05) and production (-90.3%, p<0.05) were reduced significantly at Days 7 and 14, respectively, and thereafter. Mt mass, evaluated by electron microscopy, was also reduced (-19.9%, p<0.05) at Day 7. Drp1 accumulated in mitochondria at Day 7, and S616 phosphorylation of Drp1, associated with increased activity, was increased at Day 7. Thus, PO suppresses autophagy and induces Mt dysfunction by Day 7, at which time Drp1 accumulates in mitochondria and Mt mass is decreased. To examine the functional significance of endogenous Drp1 during PO, cardiac-specific heterozygous Drp1 knock out (Drp-hetCKO) mice were subjected to TAC. At Day 7, decreases in EF (61± 2 vs 84 ± 7%, p<0.05) and increases in LVW/TL (7.22 ± 0.26 vs 5.86 ± 0.65, p<0.05) and lung weight/TL (12.01 ± 1.10 vs 6.31 ± 1.19, p<0.05) were exacerbated in Drp-hetCKO compared to in control mice. LV end diastolic pressure was significantly higher (22.0 ± 2.8 vs 5.7 ± 2.9 mmHg, p<0.05) and myocardial fibrosis (14.1 ± 2.5 vs 6.2 ± 4.3 %, p<0.05) was greater in Drp-hetCKO than in control mice. Mt mass was also significantly greater in Drp-hetCKO than in control mice (relative Mt mass, 1.21 ± 0.46 vs 1.00 ± 0.02, p<0.05). These results suggest that PO inhibits autophagy and induces mitochondrial dysfunction by Day7, which coincides with Mt accumulation of Drp1. Drp1 plays an adaptive role in this condition, mediating decreases in Mt mass and protecting the heart from dysfunction.

Abstract 168: Drp1 Accumulates in Mitochondria and Plays a Protective Role in the Heart in Response to Pressure Overload

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Akihiro Shirakabe ◽  
Yoshiyuki Ikeda ◽  
Toshiro Saito ◽  
Peiyong Zhai ◽  
Junichi Sadoshima
Keyword(s):  
Diastolic Pressure ◽  
Pressure Overload ◽  
Protective Role ◽  
Left Ventricular ◽  
Multiple Time ◽  
Lung Weight ◽  
Knock Out ◽  
Multiple Time Points ◽  
Increased Activity ◽  
Adaptive Role

Dynamin-related protein 1 (Drp1) plays an essential role in maintaining the quality control of mitochondria through mitochondrial (Mt) fission and mitophagy. We investigated how Mt function, autophagy and Drp1 are regulated in the heart during pressure overload (PO) and whether endogenous Drp1 plays an important role in regulating cardiac function. Mice were subjected to transverse aortic constriction (TAC) at multiple time points between 6 hours and 30 days. Left ventricular (LV) weight/tibial length (LVW/TL) was significantly elevated at Day 5 (TAC vs Baseline; 6.21 ± 0.28 vs 4.59 ± 0.36, p<0.05). Ejection fraction (EF) was maintained at Day 5 (79±5 vs 82±7%), but gradually decreased thereafter (30 days; 51±12%, p<0.05). LC3-II was decreased (-40.0%, p<0.05) while p62 accumulated (1.84 fold, p<0.05) significantly at Day 5. Both Mt ATP content (-65.6%, p<0.05) and production (-90.3%, p<0.05) were reduced significantly at Days 7 and 14, respectively, and thereafter. Mt mass, evaluated by electron microscopy, was also reduced (-19.9%, p<0.05) at Day 7. Drp1 accumulated in mitochondria at Day 7, and S616 phosphorylation of Drp1, associated with increased activity, was increased at Day 7. Thus, PO suppresses autophagy and induces Mt dysfunction by Day 7, at which time Drp1 accumulates in mitochondria and Mt mass is decreased. To examine the functional significance of endogenous Drp1 during PO, cardiac-specific heterozygous Drp1 knock out (Drp-hetCKO) mice were subjected to TAC. At Day 7, decreases in EF (57± 11 vs 80 ± 7%, p<0.05) and increases in LVW/TL (7.22 ± 0.26 vs 5.86 ± 0.65, p<0.05) and lung weight/TL (13.03 ± 1.09 vs 7.00 ± 1.31, p<0.05) were exacerbated in Drp-hetCKO compared to in control mice. LV end diastolic pressure was significantly higher (20.0 ± 5.7 vs 7.4 ± 3.1 mmHg, p<0.05) and myocardial fibrosis (14.1 ± 2.5 vs 6.2 ± 4.3 %, p<0.05) was greater, and Mt mass was also significantly greater in Drp-hetCKO than in control mice (relative Mt mass, 1.21 ± 0.46 vs 1.00 ± 0.02, p<0.05). These results suggest that PO inhibits autophagy and induces mitochondrial dysfunction by Day7, which coincides with Mt accumulation of Drp1. Drp1 plays an adaptive role in this condition, mediating decreases in Mt mass and protecting the heart from dysfunction.

scholarly journals Pressure Overload-Induced Cardiac Dysfunction in Aged Male Adiponectin Knockout Mice Is Associated With Autophagy Deficiency

Endocrinology ◽  
2015 ◽  
Vol 156 (7) ◽  
pp. 2667-2677 ◽  
Author(s):  
James Won Suk Jahng ◽  
Subat Turdi ◽  
Vera Kovacevic ◽  
Keith Dadson ◽  
Ren-Ke Li ◽  
...  
Keyword(s):  
Heart Failure ◽  
Western Blotting ◽  
Light Chain ◽  
Cardiac Dysfunction ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Autophagic Flux ◽  
Microtubule Associated Proteins ◽  
Cardiac Strain ◽  
Associated Proteins

Heart failure is a leading cause of death, especially in the elderly or obese and diabetic populations. Various remodeling events have been characterized, which collectively contribute to the progression of heart failure. Of particular interest, autophagy has recently emerged as an important determinant of cardiac remodeling and function. Here, we used aged, 13-month-old, male adiponectin knockout (Ad-KO) or wild-type (wt) mice subjected to aortic banding to induce pressure overload (PO). Cardiac strain analysis using speckle tracking echocardiography indicated significant dysfunction at an earlier stage in Ad-KO than wt. Analysis of autophagy by Western blotting for Light Chain 3 or microtubule-associated proteins 1B and Sequestosome 1 together with transmission electron microscopy of left ventricular tissue indicated a lack of PO-induced cardiac autophagy in Ad-KO compared with wt mice. Associated with this was mitochondrial degeneration and evidence of enhanced endoplasmic reticulum stress. Western blotting for Light Chain 3 or microtubule-associated proteins 1B, examination of flux using tandem fluoresent tagged-Light Chain 3, and analysis of lysosomal activity in H9c2 cardiac myoblasts treated with adiponectin indicated that adiponectin enhanced autophagy flux. In conclusion, adiponectin directly stimulates autophagic flux and the lack of autophagy in response to PO in aged mice lacking adiponectin may contribute to cellular events which exacerbate the development of cardiac dysfunction.

Abstract 159: Ablation of the Hypertension Candidate Gene ATP2B1 Leads To Deficient Calcium Cycling, Systolic Dysfunction and Heart Failure Following Pressure Overload

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Nicholas P Stafford ◽  
Min Zi ◽  
Ludwig Neyses ◽  
Elizabeth J Cartwright
Keyword(s):  
Heart Failure ◽  
Systolic Dysfunction ◽  
Pressure Overload ◽  
Early Response ◽  
Left Ventricular ◽  
Calcium Handling ◽  
Calcium Cycling ◽  
Lung Weight ◽  
Hypertrophic Growth ◽  
Ventricular Elastance

Mutations in ATP2B1 encoding the ubiquitous calcium extrusion pump Plasma Membrane Calcium ATPase 1 (PMCA1) have recently identified it as having the strongest association of any gene to hypertension, yet the role of PMCA1 in the pressure-overloaded heart is not known. To investigate this we generated a novel mouse line carrying cardiomyocyte-specific deletion of PMCA1 (PMCA1 cko ) and challenged them with transverse aortic constriction (TAC) alongside littermate ‘floxed’ controls (PMCA1 f/f ). After two weeks, echocardiographic analysis revealed signs of systolic dysfunction and left ventricular (LV) dilation in PMCA1 cko hearts as evidenced by reduced fractional shortening and increased diastolic diameter (both p<0.05), whilst function in PMCA1 f/f TAC controls remained preserved. This was accompanied by an increase in normalised lung weight in PMCA1 cko mice compared to sham operated and TAC controls (p<0.05) indicative of pulmonary congestion and a progression into LV failure, despite comparable hypertrophic growth amongst the two TAC cohorts. Hemodynamic analysis following LV catheterisation revealed contractility, as measured by left ventricular elastance (E es ), to be increased in controls after TAC (PMCA1 f/f TAC 12.69 ± 1.63 vs sham 7.02 ± 1.11 mmHg/μl, p<0.05), a change which was not reciprocated in knockout hearts (PMCA1 cko TAC 7.70 ± 1.19 vs sham 7.22 ± 1.55 mmHg/μl). To examine whether altered calcium handling could be the underlying cause of the observed phenotype, cardiomyocytes were isolated following one week TAC and loaded with Indo-1, prior to the onset of failure in PMCA1 cko hearts. Compatible with an increase in E es , systolic calcium levels were higher in PMCA1 f/f myocytes following pressure overload compared to sham controls (p<0.05), whilst PMCA1 cko TAC myocytes displayed equivalent peak calcium levels to their respective sham controls. These results suggest that PMCA1 may play a necessary role in enhancing calcium cycling during the early response to pressure overload, and that disrupting this gene may increase the susceptibility to heart failure under these conditions. This may provide first evidence of a novel genetic basis for the development of heart failure in a proportion of hypertensive patients.

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 O-ring-induced transverse aortic constriction (OTAC) is a new simple method to develop cardiac hypertrophy and heart failure in mice

2022 ◽  
Vol 12 (1) ◽  
Author(s):  
Yasuhisa Nakao ◽  
Jun Aono ◽  
Mika Hamaguchi ◽  
Kayo Takahashi ◽  
Tomohisa Sakaue ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Pressure Overload ◽  
Experimental Models ◽  
Left Ventricular ◽  
Transverse Aortic Constriction ◽  
Aortic Constriction ◽  
Lung Weight ◽  
Simple Method ◽  
Fractional Shortening

AbstractSuture-based transverse aortic constriction (TAC) in mice is one of the most frequently used experimental models for cardiac pressure overload-induced heart failure. However, the incidence of heart failure in the conventional TAC depends on the operator’s skill. To optimize and simplify this method, we proposed O-ring-induced transverse aortic constriction (OTAC) in mice. C57BL/6J mice were subjected to OTAC, in which an o-ring was applied to the transverse aorta (between the brachiocephalic artery and the left common carotid artery) and tied with a triple knot. We used different inner diameters of o-rings were 0.50 and 0.45 mm. Pressure overload by OTAC promoted left ventricular (LV) hypertrophy. OTAC also increased lung weight, indicating severe pulmonary congestion. Echocardiographic findings revealed that both OTAC groups developed LV hypertrophy within one week after the procedure and gradually reduced LV fractional shortening. In addition, significant elevations in gene expression related to heart failure, LV hypertrophy, and LV fibrosis were observed in the LV of OTAC mice. We demonstrated the OTAC method, which is a simple and effective cardiac pressure overload method in mice. This method will efficiently help us understand heart failure (HF) mechanisms with reduced LV ejection fraction (HFrEF) and cardiac hypertrophy.

P1613Brown adipose tissue dysfunction has a critical role for the development of heart failure in murine pressure overload model

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
Y Yoshida ◽  
I Shimizu ◽  
K Walsh ◽  
T Minamino
Keyword(s):  
Heart Failure ◽  
Adipose Tissue ◽  
Body Temperature ◽  
Cardiac Dysfunction ◽  
Critical Role ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Failing Heart ◽  
Brown Adipose

Abstract Prognosis of severe heart failure is unacceptably high, and it is our urgent task to find therapies for this critical condition. It has been reported that low body temperature predicts poor clinical outcomes in patients with heart failure, however, underlying mechanisms and pathological implications are largely unknown. Brown adipose tissue (BAT) was initially characterized as a heat generating organ, and studies suggest that BAT has crucial roles for the maintenance of systemic metabolic health. Here we show that BAT dysfunction develops in a murine thoracic aortic constriction (TAC) model, and has a causal role for promoting pathologies in failing heart. TAC operation led to a significant reduction both in intraperitoneal and subcutaneous temperature. TUNEL-positive cells significantly increased in BAT during left ventricular (LV)-pressure overload, and in-vitro studies with differentiated brown adipocytes suggested that the chronic activation of adrenergic signaling promotes apoptosis in these cells. Gain of BAT function model, generated with BAT implantation into peritoneal cavity, improved thermogenesis and ameliorated cardiac dysfunction in TAC. In contrast, genetic model of BAT dysfunction promoted cardiac dysfunction. Metabolomic analyses showed that BAT dysfunction led to an increase of oxidized choline that promoted metabolic dysfunction in the failing heart. Electron microscope study showed that oxidized choline induced mitochondrial dysfunction in vitro as well as in vivo settings. Extracellular flux analyzerindicated that oxidized choline suppresses oxidative phosphorylation in mitochondria. We found that dilated cardiomyopathy patients have lower body temperature, and confirmed by metabolomic study that both choline and oxidized choline are increased in circulation. Maintenance of BAT homeostasis and suppression of oxidized choline would become a novel therapeutic target for heart failure.

Abstract 289: Retinoblastoma Gene Deletion Promotes Cardiac Dysfunction, Fibrosis and Apoptosis in Response to Pressure Overload

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Paul B Ammann ◽  
Takanobu Yamamoto ◽  
Peiyong Zhai ◽  
Junichi Sadoshima
Keyword(s):  
Cardiac Hypertrophy ◽  
Cardiac Dysfunction ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Heart Weight ◽  
Tunel Staining ◽  
Pressure Gradients ◽  
Lung Weight ◽  
Rb Protein

The retinoblastoma (Rb) protein is a universal cell cycle regulator in mammals. When the Rb protein is phosphorylated by Cyclins/Cdks, it dissociates from E2F, and Rb-dependent E2F repression is subsequently inactivated. Furthermore, the Rb protein has also been implicated in the regulation of cardiac hypertrophy and apoptosis in cardiomyocytes (CMs). To elucidate the role of Rb in response to mechanical stress, we conducted transverse aortic constriction (TAC) in cardiac-specific Rb knockout mice (cRb-KO) in vivo (C57BL/6J). Cardiac-specific deletion of Rb was achieved by crossing Rb flox/flox mice with αMHC-Cre mice. Under basal conditions, 3- to 5-month-old cRb-KO mice showed increased heart weight (HW) (left ventricular weight/ tibial length (TL): 5.93 ± 029 vs. 4.76 ± 0.14, p< 0.01), increased apoptosis as determined by TUNEL staining (0.12% vs. 0.02%, p< 0.05) and a trend towards cardiac dysfunction (-dP/dt: 4320 ± 388 vs. 5933 ± 489 mmHg/sec, p < 0.05) compared to control mice (Rb flox/flox) Following 2 weeks of TAC, cRb-KO mice showed increased heart weight (HW/TL: 8.58 ± 0.35 vs. 7.50 ± 0.24, p < 0.05), cardiac dysfunction (ejection fraction (EF): 51.1% ± 4.0 vs. 74.3% ± 0.9, p < 0.01) , increased apoptosis as determined by TUNEL staining (0.48% vs. 0.05%, p < 0.01) and increased fibrosis as determined by Masson’s Trichrome staining (1.84% vs. 1.03%, p < 0.05) compared to Rb flox/flox mice after TAC. In response to 4 weeks of TAC, cRb-KO mice showed increased heart weight (HW/TL: 12.93 ± 085 vs. 9.32 ± 0.34, p < 0.01), lung weight (LW) (LW/TL: 18.35 ± 2.66 vs. 10.21 ± 1.93, p < 0.01), cardiac dysfunction (EF: 34.5% ± 8.3 vs. 64.3% ± 8.9, p < 0.01), increased apoptosis as determined by TUNEL staining (0,42% vs. 0,18%, p < 0.05) and increased fibrosis as determined by Masson’s Trichrome staining (4.2 % vs. 1.1 %, p < 0.05) compared to Rb flox/flox mice after TAC. Pressure gradients were similar between the cRb-KO mice submitted to 2 and 4 weeks of TAC and their respective controls. In conclusion, our results suggest that endogenous Rb plays an important role in mediating cell survival in CMs and negatively regulates cardiac hypertrophy at baseline. Furthermore, we showed that the Rb protein is important for the maintenance of cardiac function in response to pressure overload.

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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