Abstract 18122: Mir-206 Plays an Important Role in Mediating Pressure Overload-induced Cardiac Hypertrophy

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Sebstiano Sciarretta ◽  
Yanfei Yang ◽  
Dominic P Del Re ◽  
Junichi Sadoshima
Keyword(s):  
Cardiac Hypertrophy ◽  
Sequence Similarity ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Pcr Analysis ◽  
Mouse Heart ◽  
Sham Operation ◽  
Hippo Signaling ◽  
Qrt Pcr

Introduction: Expression of miR-206 is upregulated by YAP, a key transcription co-factor controlled by the Hippo signaling pathway, and mediates YAP-induced hypertrophy and survival of cardiomyocytes. Although miR-206 is known to promote hypertrophy of skeletal muscle, the role of miR-206 in the heart under clinically relevant conditions in vivo remains unknown. We investigated the role of miR-206 in mediating cardiac hypertrophy in response to pressure overload (PO). Results: The level of miR-206 in the mouse heart, as evaluated by qRT-PCR, was upregulated 2.9 fold (p<0.05) 7 days after transverse aortic constriction (TAC) compared to sham operation. In order to evaluate the involvement of miR-206 in cardiac hypertrophy, wild-type C57B/6J mice were administered LNA inhibitor designed to selectively inhibit miR-206, or control scrambled LNA, by tail vein injection. Specificity of the LNA inhibitor was confirmed by qRT-PCR analysis of miRNA expression 48 hours after treatment. Notably, the LNA inhibitor did not affect the level of miR-1, which has a sequence similarity with miR-206. After 48 hours, mice from both treatment groups were subjected to sham operation or TAC. After 7 days of TAC, echocardiography was performed and mice were sacrificed. Upregulation of myocardial miR-206 expression levels after 7 days TAC observed in LNA control-treated mice was completely abolished in LNA-anti-206 -treated mice. A significant increase in left ventricular weight/tibial length (mg/mm) in LNA control-treated mice following TAC was observed (sham vs TAC: 3.7, 4.8, p<0.05); however, no increase was observed in LNA-anti-206 -treated mice (3.8, 3.8). We also noted significant differences in chamber wall thickness (mm) between the LNA-control and LNA-anti-206-treated TAC groups (diastolic posterior wall 0.91, 0.61, p<0.05). Additionally, cardiomyocyte cross sectional area (1.23, 0.9, p<0.05) and ANF expression (2.5, 1.3, P<0.05) were significantly increased in the LNA control-treated TAC group, and these responses were attenuated in the LNA-anti-206-treated mice. Conclusions: These data demonstrate that inhibition of miR-206 impairs PO-induced hypertrophy and indicates that miR-206 is an important endogenous mediator of heart growth in response to PO.

scholarly journals Leonurine Attenuates Pressure-Overload Cardiac Hypertrophy Induced By Abdominal Aortic Constriction In Rats

2021 ◽  
Author(s):  
Ding Xiaoli ◽  
Yuan Qingqing ◽  
Qian Haibing
Keyword(s):  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Pressure Overload ◽  
Ventricular Myocardium ◽  
Left Ventricular ◽  
Left Ventricular Myocardium ◽  
Ang Ii ◽  
Aortic Constriction ◽  
Qrt Pcr ◽  
Abdominal Aortic

Abstract Background: Myocardial hypertrophy occurs in many cardiovascular diseases. Leonurine (Leo) is commonly used for cardiovascular and cerebrovascular diseases. However, whether it can prevent cardiac hypertrophy is not known. The aim of this study was to investigate the effect and mechanism of Leonurine (Leo) against pressure-overload cardiac hypertrophy induced by abdominal aortic constriction (AAC) in rats. Methods: To answer this question, we prove it in the following way: Cardiac function was evaluated by hemodynamic; the left ventricle enlargement was measured by heart weight index (HWI) and left ventricular mass index (LVWI); myocardial tissue changes and myocardial cell diameter (MD) were determined by Hematoxylin and eosin (HE) staining; theβ-myosin heavy chain(β-MHC)and atrial natriuretic factor (ANF), which are recognized as a marker of cardiac hypertrophy, were determined by Real-time quantitative PCR (qRT-PCR), then another gene phospholipase C (PLC), inositol triphosphate (IP3), which associated with RAS were determined by Western blot(WB). angiotensin II (Ang II), angiotensin II type 1 receptor (AT1R) were determined by ELISA, WB and qRT-PCR methods. Finally, we measured the level of Ca2+ by microplate method and the protooncogene c-fos and c-myc mRNA in left ventricular myocardium by qRT-PCR.Results: Compare with control group, Leonurine can improve systolic dysfunction; inhibit the increase of left cardiac; inhibit myocardial cells were abnormally large and restrain the changes of cardiac histopathology; decrease the expression of β-MHC, ANF, Ang II, AT1R, c-fos and c-myc mRNA and the protein levels of PLC, IP3, AngII and AT1R in left ventricular myocardium, in addition, the content of Ca2+ also decrease. Conclusion: Therefore, Leonurine can inhibit cardiac hypertrophy induced by AAC and its effects may be associated with RAS.

Abstract P189: RhoA Functions as an Antihypertrophic Switch in the Mouse Heart

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Davy Vanhoutte ◽  
Jop Van Berlo ◽  
Allen J York ◽  
Yi Zheng ◽  
Jeffery D Molkentin
Keyword(s):  
Cardiac Hypertrophy ◽  
Pressure Overload ◽  
Small Gtpase ◽  
Mouse Heart ◽  
Activity Levels ◽  
Lung Weight ◽  
Pathological Cardiac Hypertrophy ◽  
Rhoa Protein

Background. Small GTPase RhoA has been previously implicated as an important signaling effector within the cardiomyocyte. However, recent studies have challenged the hypothesized role of RhoA as an effector of cardiac hypertrophy. Therefore, this study examined the in vivo role of RhoA in the development of pathological cardiac hypertrophy. Methods and results . Endogenous RhoA protein expression and activity levels (GTP-bound) in wild-type hearts were significantly increased after pressure overload induced by transverse aortic constriction (TAC). To investigate the necessity of RhoA within the adult heart, RhoA-LoxP-targeted (RhoA flx/flx ) mice were crossed with transgenic mice expressing Cre recombinase under the control of the endogenous cardiomyocyte-specific β-myosin heavy chain (β-MHC) promoter to generate RhoA βMHC-cre mice. Deletion of RhoA with β-MHC-Cre produced viable adults with > 85% loss of RhoA protein in the heart, without altering the basic architecture and function of the heart compared to control hearts, at both 2 and 8 months of age. However, subjecting RhoA βMHC-cre hearts to 2 weeks of TAC resulted in marked increase in cardiac hypertrophy (HW/BW (mg/g): 9.5 ± 0.3 for RhoA βMHC-cre versus 7.7 ± 0.4 for RhoA flx/flx ; and cardiomyocyte size (mm 2 ): 407 ± 21 for RhoA βMHC-cre versus 262 ± 8 for RhoA flx/flx ; n ≥ 8 per group; p<0.01) and a significantly increased fibrotic response. Moreover, RhoA βMHC-cre hearts transitioned more quickly into heart failure whereas control mice maintained proper cardiac function (fractional shortening (%): 23.3 ± 1.2 for RhoA βMHC-cre versus 29.3 ± 1.2 for RhoA flx/flx ; n ≥ 8 per group; p<0.01; 12 weeks after TAC). The latter was further associated with a significant increase in lung weight normalized to body weight and re-expression of the cardiac fetal gene program. In addition, these mice also displayed greater cardiac hypertrophy in response to 2 weeks of angiotensinII/phenylephrine infusion. Conclusion. These data identify RhoA as an antihypertrophic molecular switch in the mouse heart.

scholarly journals Orai1 Channel Inhibition Preserves Left Ventricular Systolic Function and Normal Ca 2+ Handling After Pressure Overload

Circulation ◽  
2020 ◽  
Vol 141 (3) ◽  
pp. 199-216 ◽  
Author(s):  
Fiona Bartoli ◽  
Marc A. Bailey ◽  
Baptiste Rode ◽  
Philippe Mateo ◽  
Fabrice Antigny ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Systolic Function ◽  
Systolic Dysfunction ◽  
Pressure Overload ◽  
Left Ventricular Systolic Function ◽  
Left Ventricular ◽  
Specific Expression ◽  
Channel Inhibition

Background: Orai1 is a critical ion channel subunit, best recognized as a mediator of store-operated Ca 2+ entry (SOCE) in nonexcitable cells. SOCE has recently emerged as a key contributor of cardiac hypertrophy and heart failure but the relevance of Orai1 is still unclear. Methods: To test the role of these Orai1 channels in the cardiac pathophysiology, a transgenic mouse was generated with cardiomyocyte-specific expression of an ion pore-disruptive Orai1 R91W mutant (C-dnO1). Synthetic chemistry and channel screening strategies were used to develop 4-(2,5-dimethoxyphenyl)-N-[(pyridin-4-yl)methyl]aniline (hereafter referred to as JPIII), a small-molecule Orai1 channel inhibitor suitable for in vivo delivery. Results: Adult mice subjected to transverse aortic constriction (TAC) developed cardiac hypertrophy and reduced ventricular function associated with increased Orai1 expression and Orai1-dependent SOCE (assessed by Mn 2+ influx). C-dnO1 mice displayed normal cardiac electromechanical function and cellular excitation-contraction coupling despite reduced Orai1-dependent SOCE. Five weeks after TAC, C-dnO1 mice were protected from systolic dysfunction (assessed by preserved left ventricular fractional shortening and ejection fraction) even if increased cardiac mass and prohypertrophic markers induction were observed. This is correlated with a protection from TAC-induced cellular Ca 2+ signaling alterations (increased SOCE, decreased [Ca 2+ ] i transients amplitude and decay rate, lower SR Ca 2+ load and depressed cellular contractility) and SERCA2a downregulation in ventricular cardiomyocytes from C-dnO1 mice, associated with blunted Pyk2 signaling. There was also less fibrosis in heart sections from C-dnO1 mice after TAC. Moreover, 3 weeks treatment with JPIII following 5 weeks of TAC confirmed the translational relevance of an Orai1 inhibition strategy during hypertrophic insult. Conclusions: The findings suggest a key role of cardiac Orai1 channels and the potential for Orai1 channel inhibitors as inotropic therapies for maintaining contractility reserve after hypertrophic stress.

Abstract 17904: Deficiency of Yes-associated Protein Promotes Cardiac Dysfunction in Response to Pressure Overload in the Mouse Heart

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Jaemin Byun ◽  
Dominic P Del Re ◽  
Peiyong Zhai ◽  
Akihiro Shirakabe ◽  
Junichi Sadoshima
Keyword(s):  
Cardiac Hypertrophy ◽  
Mammalian Cells ◽  
Diastolic Pressure ◽  
Systolic Function ◽  
Pressure Overload ◽  
Wall Stress ◽  
Left Ventricular ◽  
Lv Function ◽  
Mouse Heart ◽  
And Control

Yes-Associated Protein (YAP), a downstream effector of the Hippo pathway, plays an important role in regulating cell proliferation and survival in mammalian cells. We have shown that cardiac-specific loss of YAP leads to increased cardiomyocyte (CM) apoptosis and impaired hypertrophy during chronic myocardial infarction in the mouse heart. However, it remains unclear whether YAP mediates hypertrophy of individual CMs under stress conditions in vivo. We hypothesized that endogenous YAP plays an essential role in mediating hypertrophy and survival of CMs in response to pressure overload (PO). Three-month-old YAP+/fl;α-MHC-Cre (YAP-cKO) and YAP+/fl (control) mice were subjected to transverse aortic constriction (TAC). Two weeks later, YAP-cKO and control mice developed similar levels of cardiac hypertrophy (left ventricular (LV) weight/tibia length: 7.27±0.38, 6.93±0.29) compared to sham (5.08±0.14, 4.07±0.33). LV CM cross sectional area was similarly increased by TAC in YAP-cKO and control mice compared to their respective shams. Induction of fetal-type genes, such as Anf and Myh7, was also similar in YAP-cKO and control mice. YAP-cKO and control mice exhibited similar baseline LV systolic function (ejection fraction (EF): 75, 76%). YAP-cKO mice had significantly decreased LV function after TAC compared to Sham-control mice (EF: 51%, 76%, p<0.05) and TAC-control mice (75%, p<0.05). LV end diastolic pressure (LVEDP, mmHg) was significantly increased (19.3 ±3.2, 9.8±1.6, p<0.05), and LV +dP/dt (mmHg/s, 7250±588, 9500±453, p<0.01) and -dP/dt (mmHg/s, 6000±433, 7781± 314, p<0.05) were significantly decreased in YAP-cKO compared to in control mice after TAC. LV end diastolic diameter (mm) was significantly greater in YAP-cKO than in control mice after TAC (3.95±0.11, 3.35±0.15, p<0.05), whereas LV pressure was similar, suggesting that LV wall stress was elevated in YAP-cKO compared to in control mice. Since cardiac hypertrophy in YAP-cKO mice is similar to that in control mice despite elevated wall stress, the lack of YAP appears to limit the extent of cardiac hypertrophy in response to increased wall stress. These data suggest that endogenous YAP plays an important role in mediating adaptive hypertrophy and protecting the heart against PO.

Disruption of actin dynamics regulated by Rho effector mDia1 attenuates pressure overload-induced cardiac hypertrophic responses and exacerbates dysfunction

2020 ◽  
Author(s):  
Ichitaro Abe ◽  
Takeshi Terabayashi ◽  
Katsuhiro Hanada ◽  
Hidekazu Kondo ◽  
Yasushi Teshima ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Neonatal Rat ◽  
Actin Dynamics ◽  
Heart Weight ◽  
Sham Operation ◽  
Compensatory Response ◽  
Cross Sectional

Abstract Aims Cardiac hypertrophy is a compensatory response to pressure overload, leading to heart failure. Recent studies have demonstrated that Rho is immediately activated in left ventricles after pressure overload and that Rho signalling plays crucial regulatory roles in actin cytoskeleton rearrangement during cardiac hypertrophic responses. However, the mechanisms by which Rho and its downstream proteins control actin dynamics during hypertrophic responses remain not fully understood. In this study, we identified the pivotal roles of mammalian homologue of Drosophila diaphanous (mDia) 1, a Rho-effector molecule, in pressure overload-induced ventricular hypertrophy. Methods and results  Male wild-type (WT) and mDia1-knockout (mDia1KO) mice (10–12 weeks old) were subjected to a transverse aortic constriction (TAC) or sham operation. The heart weight/tibia length ratio, cardiomyocyte cross-sectional area, left ventricular wall thickness, and expression of hypertrophy-specific genes were significantly decreased in mDia1KO mice 3 weeks after TAC, and the mortality rate was higher at 12 weeks. Echocardiography indicated that mDia1 deletion increased the severity of heart failure 8 weeks after TAC. Importantly, we could not observe apparent defects in cardiac hypertrophic responses in mDia3-knockout mice. Microarray analysis revealed that mDia1 was involved in the induction of hypertrophy-related genes, including immediate early genes, in pressure overloaded hearts. Loss of mDia1 attenuated activation of the mechanotransduction pathway in TAC-operated mice hearts. We also found that mDia1 was involved in stretch-induced activation of the mechanotransduction pathway and gene expression of c-fos in neonatal rat ventricular cardiomyocytes (NRVMs). mDia1 regulated the filamentous/globular (F/G)-actin ratio in response to pressure overload in mice. Additionally, increases in nuclear myocardin-related transcription factors and serum response factor were perturbed in response to pressure overload in mDia1KO mice and to mechanical stretch in mDia1 depleted NRVMs. Conclusion  mDia1, through actin dynamics, is involved in compensatory cardiac hypertrophy in response to pressure overload.

Role of microtubules in myocyte contractile dysfunction during cardiac hypertrophy in the rat

1996 ◽  
Vol 271 (5) ◽  
pp. H1978-H1987 ◽  
Author(s):  
Y. Ishibashi ◽  
H. Tsutsui ◽  
S. Yamamoto ◽  
M. Takahashi ◽  
K. Imanaka-Yoshida ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Western Blot ◽  
Blot Analysis ◽  
Western Blot Analysis ◽  
Contractile Function ◽  
Pressure Overload ◽  
Progressive Increase ◽  
Left Ventricular ◽  
Contractile Dysfunction

We have shown that increased microtubules cause myocyte contractile dysfunction in feline right ventricular pressure-overload hypertrophy. To investigate the association between the progression of cardiac hypertrophy and microtubules and to delineate the role of microtubules in contractile defects in hypertrophied myocytes, we assessed the amounts of free and polymerized tubulin proteins, using Western blot analysis and immunofluorescence micrograph, and evaluated the sarcomere mechanics of myocytes isolated from rats with pressure-overload left ventricular (LV) hypertrophy. Total and polymerized tubulins were progressively and persistently increased in LV after the imposition of pressure overload. The increase in microtubules was associated with the development and progression of hypertrophy and not the immediate response to the stress loading to the myocardium. The contractile function of hypertrophied myocytes was depressed in parallel with the increase in microtubules. Depolymerization of microtubules normalized the initially depressed LV myocyte contractile function. Thus the progressive increase of microtubule density during LV hypertrophy due to persistent pressure overloading to the myocardium may cause the consequent myocyte contractile dysfunction.

Abstract 15687: Loss of Tribbles 3 (TRIB3) Attenuates Pressure-Overload Induced Myocardial Hypertrophy

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Eltyeb Abdelwahid ◽  
Rongxue Wu ◽  
Amy K Rines ◽  
Hossein Ardehali
Keyword(s):  
Cardiac Hypertrophy ◽  
Wall Thickness ◽  
Pressure Overload ◽  
Cellular Metabolism ◽  
Left Ventricular ◽  
Left Ventricular Wall ◽  
Heart Weight ◽  
Sham Operation ◽  
Ventricular Wall ◽  
Exact Function

Introduction: Tribbles 3 (TRIB3) is a pseudokinase that regulates several biological functions such as cell proliferation and differentiation through its role in cellular metabolism. TRIB3 expression is modulated by various signals such as endoplasmic reticulum (ER) stress, nutrient availability, and insulin. The exact function of TRIB3 in the heart is largely unknown. We hypothesized that loss of TRIB3 protects against cardiac hypertrophy through its role in the regulation of cellular metabolism. Results: To elucidate the role of TRIB3 loss in the heart, we generated TRIB3 knock-out (KO) mice. The animals were then subjected to transverse aortic constriction (TAC) and sham-surgery control. In the sham operation groups, there was no hypertrophy in both TRIB3-/- and Wild type (WT) age matched control mice. WT mice subjected to TAC (WT-TAC) showed cardiac hypertrophy evidenced by increased heart weight/body weight, increased left ventricular wall thickness and increased cardiomyocyte cross-sectional area. These hypertrophic findings were significantly reduced in TRIB3 KO-TAC hearts (P<0.05). Echocardiographic analysis revealed increased diastolic interventricular septum wall (IVSd), increased left ventricular wall posterior wall thickness (LVPWd) and decreased fractional shortening (FS) in WT-TAC mice, however these changes were significantly blocked in TRIB3 KO-TAC group suggesting that TAC-induced left ventricular hypertrophy and dysfunction was attenuated in TRIB3 KO mice (P<0.05). The blunted response to hypertrophy seen in TRIB3 KO-TAC group was further demonstrated by the significant decrease in mRNA expression of myocardial hypertrophic markers (ANP, BNP and MHC) in TRIB3 KO-TAC hypertrophied left ventricles compared to WT-TAC control subjects (P<0.05). Furthermore, our data indicated increased TRIB3 expression in the WT-TAC hypertrophied left ventricles compared to WT-Sham group (P<0.05). Conclusions: The present study demonstrated that TRIB3 expression is promoted in hypertrophied hearts. TRIB3 deletion suppresses cardiac pressure overload-induced hypertrophy. Thus, TRIB3 is a novel target that plays a role in cardiac hypertrophy and maladaptation following pressure overload.

Abstract P136: E2F2/4 Regulated by Serine 21 Phosphorylation of GSK-3α Play Compensatory Roles During Pressure Overload

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Takanobu Yamamoto ◽  
Yasuhiro Maejima ◽  
Peiyong Zhai ◽  
Takahisa Matsuda ◽  
Junichi Sadoshima
Keyword(s):  
Cardiac Hypertrophy ◽  
Glycogen Synthase ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Causative Role ◽  
Serine Threonine Kinase ◽  
Lv Dysfunction ◽  
Cardiac Phenotype ◽  
And Function

Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase with two isoforms, alpha and beta, which have distinct functions in cardiomyocytes (CMs). GSK-3alpha is phosphorylated at S21 during pressure overload (PO), and inhibition of S21 phosphorylation in GSK-3alpha S21A knock-in (alpha−KI) mice promotes hypertrophy and heart failure in response to PO, accompanied by decreases in the total number of CMs in the heart. Since GSK-3alpha downregulates cyclinD1 in the nucleus, GSK-3alpha may negatively regulate E2F-mediated transcription. Reporter gene assays showed that the transcriptional activity of E2F was increased by GSK-3alpha knockdown (1.75 fold, p<0.05). To evaluate the role of E2F isoforms in regulating cardiac hypertrophy and function during PO, E2F1−/−, E2F2−/+, E2F4−/+, and wild type (WT) mice were subjected to transverse aortic constriction (TAC). Left ventricular (LV) weight/ tibial length (LVW/TL) was significantly greater and LV ejection fraction (LVEF) was significantly decreased in both E2F2−/+ and E2F4−/+ after 2 weeks of TAC (LVW/TL: E2F2−/+=7.1±0.3, E2F4−/+=7.0±0.4, WT=5.9±0.3, p<0.05 vs. WT; LVEF: E2F2−/+=53±1%, E2F4−/+=61±2%, WT=75±1%, p<0.05 vs. WT). Thus, downregulation of either E2F2 or E2F4 induced a phenotype similar to that of alpha−KI in response to TAC. To examine the causative role of E2F2/E2F4 downregulation in mediating the cardiac phenotype in alpha-KI mice, adenovirus (Ad) harboring either E2F2 or E2F4 was injected into alpha-KI hearts. Rescue with E2F2 or E2F4 attenuated cardiac hypertrophy (LVW/TL: alpha−KI+E2F2=7.1±0.4, alpha−KI+E2F4=7.3±0.3, alpha−KI+LacZ=8.7±0.4, p<0.05 vs. alpha−KI+LacZ) and improved LV dysfunction (LVEF: alpha−KI+E2F2=66±3%, alpha−KI+E2F4=60±2%, alpha−KI+LacZ=39±2%, p<0.05 vs. alpha−KI+LacZ) in alpha−KI mice under PO conditions. Injection of either Ad-E2F2 or Ad-E2F4, but not of Ad-LacZ, significantly increased the number of Ki67-positive myocytes in the alpha-KI mice (alpha-KI+LacZ =0.7±0.3%, alpha-KI+E2F2=10.4±2.3%, alpha-KI+E2F4=9.2±1.5%, p<0.05 vs. alpha-KI+LacZ). These results suggest that maintaining the activity of E2F2 and E2F4 through S21 phosphorylation of GSK-3alpha plays an essential role in preserving cardiac function during PO.

scholarly journals How does pressure overload cause cardiac hypertrophy and dysfunction? High-ouabain affinity cardiac Na+ pumps are crucial

2017 ◽  
Vol 313 (5) ◽  
pp. H919-H930 ◽  
Author(s):  
Mordecai P. Blaustein
Keyword(s):  
Cardiac Hypertrophy ◽  
Ventricular Hypertrophy ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Genetically Engineered ◽  
Wild Type ◽  
Ouabain Binding ◽  
Transaortic Constriction ◽  
Endogenous Ouabain

Left ventricular hypertrophy is frequently observed in hypertensive patients and is believed to be due to the pressure overload and cardiomyocyte stretch. Three recent reports on mice with genetically engineered Na+ pumps, however, have demonstrated that cardiac ouabain-sensitive α2-Na+ pumps play a key role in the pathogenesis of transaortic constriction-induced hypertrophy. Hypertrophy was delayed/attenuated in mice with mutant, ouabain-resistant α2-Na+ pumps and in mice with cardiac-selective knockout or transgenic overexpression of α2-Na+ pumps. The latter, seemingly paradoxical, findings can be explained by comparing the numbers of available (ouabain-free) high-affinity (α2) ouabain-binding sites in wild-type, knockout, and transgenic hearts. Conversely, hypertrophy was accelerated in α2-ouabain-resistant (R) mice in which the normally ouabain-resistant α1-Na+ pumps were mutated to an ouabain-sensitive (S) form (α1S/Sα2R/R or “SWAP” vs. wild-type or α1R/R α2S/S mice). Furthermore, transaortic constriction-induced hypertrophy in SWAP mice was prevented/reversed by immunoneutralizing circulating endogenous ouabain (EO). These findings show that EO and its receptor, ouabain-sensitive α2, are critical factors in pressure overload-induced cardiac hypertrophy. This complements reports linking elevated plasma EO to hypertension, cardiac hypertrophy, and failure in humans and elucidates the underappreciated role of the EO-Na+ pump pathway in cardiovascular disease.

Abstract 13114: P22 phox Protects the Heart Against Pressure Overload

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Yasuki Nakada ◽  
Wataru Mizushima ◽  
Yanfei Yang ◽  
Peiyong Zhai ◽  
Shinichi Oka ◽  
...  
Keyword(s):  
Control Mouse ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Sham Operation ◽  
Cysteine Oxidation ◽  
Isolated Cardiomyocytes ◽  
Ventricular Ejection Fraction ◽  
Cardiac Phenotype

Introduction: p22 phox forms a complex with NADPH oxidases, major sources of O 2 - and H 2 O 2 . However, the role of p22 phox during stress remains to be elucidated. Purpose: To investigate the role of endogenous p22 phox during pressure overload (PO). Methods and Results: The level of p22 phox protein in isolated cardiomyocytes after 4 weeks of transverse aortic constriction (TAC) was significantly higher than after sham operation (1.7-fold, p<0.05). The cardiac phenotype of cardiac-specific p22 phox knockout ( p22 phox cKO) mice was normal at baseline. However, four weeks after TAC, p22 phox cKO mice exhibited a lower left ventricular ejection fraction (32.0±10.0 vs 53.2±8.4%, p<0.05), a higher lung weight to tibial length ratio (23.0±6.0 vs 13.1±6.6, p<0.05), and more interstitial fibrosis (6.1±1.0 vs 4.4±1.1%, p<0.05) than control mice, indicating that the loss of p22 phox exacerbates TAC-induced cardiac dysfunction. The level of oxidative stress in the heart, evaluated by dityrosine immunoblot, was significantly lower in p22 phox cKO mice than in control mice (0.71±0.04 vs 1.00±0.04, p<0.01). The peak Ca 2+ amplitude in isolated cardiomyocytes was lower in p22 phox cKO mice than in control mice at baseline (2.4±0.1 vs 3.0±0.2, p<0.01). Although mRNA expression of SERCA2a did not differ, there was significantly less SERCA2a protein in p22 phox cKO mice than in control mice (0.62±0.10 vs 1.00±0.23, p<0.01) at baseline. The amount of biotinylated iodoacetamide labeled SERCA2a was significantly smaller in p22 phox cKO hearts than in control mouse hearts (0.4-fold, p<0.01), indicating that cysteine residues in SERCA2a are oxidized to a greater extent in p22 phox cKO hearts than in control mouse hearts. Since cysteine oxidation decreases the stability of SERCA2a, our results suggest that p22 phox stabilizes SERCA2a by preventing cysteine oxidation. Conclusions: Endogenous p22 phox is protective against PO, possibly by maintaining SERCA2a stability.

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