Omentin functions to attenuate cardiac hypertrophic response

Cardiac hypertrophy occurs in many obesity-related conditions. Omentin is an adipose-derived plasma protein that is downregulated under obese conditions. Here, we investigated whether omentin modulates cardiac hypertrophic responses in vivo and in vitro. Systemic administration of an adenoviral vector expressing human omentin (Ad-OMT) to wild-type (WT) mice led to the attenuation of cardiac hypertrophy, fibrosis and ERK phosphorylation induced by transverse aortic constriction (TAC) or angiotensin II infusion. In cultured cardiomyocytes, stimulation with phenylephrine (PE) led to an increase in myocyte size, which was prevented by pretreatment with human omentin protein. Pretreatment of cardiomyocytes with omentin protein also reduced ERK phosphorylation in response to PE stimulation. Ad-OMT enhanced phosphorylation of AMP-activated protein kinase (AMPK) in the heart of WT mice after TAC operation. Blockade of AMPK activation by transduction with dominant-negative mutant forms of AMPK reversed the inhibitory effect of omentin on myocyte hypertrophy and ERK phosphorylation following PE stimulation. Moreover, fat-specific transgenic mice expressing human omentin showed reduced cardiac hypertrophy and ERK phosphorylation following TAC surgery compared to littermate controls. These data suggest that omentin functions to attenuate the pathological process of myocardial hypertrophy via the activation of AMPK in the heart, suggesting that omentin may represent a target molecule for the treatment of cardiac hypertrophy.     

Diacylglycerol kinase zeta attenuates pressure overload-induced cardiac hypertrophy.

BACKGROUND: The Gaq protein-coupled receptor (GPCR) signaling pathway, which includes diacylglycerol (DAG) and protein kinase C (PKC), plays a critical role in the development of cardiac hypertrophy and heart failure. DAG kinase (DGK) phosphorylates DAG and controls cellular DAG levels, thus acting as a regulator of GPCR signaling. It has been previously reported that DGK inhibited GPCR agonist-induced activation of the DAG-PKC signaling and subsequent cardiomyocyte hypertrophy, so the purpose of this study was to examine whether DGK modifies the development of cardiac hypertrophy induced by pressure overload. METHODS AND RESULTS: Thoracic transverse aortic constriction (TAC) was created in transgenic mice with cardiac-specific overexpression of DGKzeta (DGKzeta-TG) and wild-type (WT) mice. Increases in heart weight at 4 weeks after TAC were attenuated in DGKzeta-TG mice compared with WT mice. Increases in interventricular septal thickness, dilatation of the left ventricular cavity, and decreases in left ventricular systolic function in WT mice were observed with echocardiography at 4 weeks after TAC surgery. However, these structural and functional changes after TAC were attenuated in DGKzeta-TG mice. In WT mice, cardiac fibrosis and up-regulation of profibrotic genes, such as transforming growth factor-beta1, collagen type I, and collagen type III, were observed at 4 weeks after TAC. However, cardiac fibrosis and gene induction of type I and type III collagens, but not transforming growth factor-beta1, were blocked in DGKzeta-TG mice. CONCLUSION: These results are the first in vivo evidence that DGKzeta suppresses cardiac hypertrophy and fibrosis and prevents impaired left ventricular systolic function caused by pressure overload.     

Adiponectin deficiency exacerbates cardiac dysfunction following pressure overload through disruption of an AMPK-dependent angiogenic response

Although increasing evidence indicates that an adipokine adiponectin exerts protective actions on heart, its effects on coronary angiogenesis following pressure overload have not been examined previously. Because disruption of angiogenesis during heart growth leads to contractile dysfunction and heart failure, we hypothesized that adiponectin modulates cardiac remodeling in response to pressure overload through its ability to regulate adaptive angiogenesis. Adiponectin-knockout (APN-KO) and wild-type (WT) mice were subjected to pressure overload caused by transverse aortic constriction (TAC). APN-KO mice exhibited greater cardiac hypertrophy, pulmonary congestion, left ventricular (LV) interstitial fibrosis and LV systolic dysfunction after TAC surgery compared with WT mice. APN-KO mice also displayed reduced capillary density in the myocardium after TAC, which was accompanied by a significant decrease in expression of vascular endothelial growth factor (VEGF) and phosphorylation of AMP-activated protein kinase (AMPK). Inhibition of AMPK in WT mice resulted in aggravated LV systolic function, attenuated myocardial capillary density and decreased VEGF expression in response to TAC. The adverse effects of AMPK inhibition on cardiac function and angiogenic response following TAC were diminished in APN-KO mice relative to WT mice. Moreover, adenovirus-mediated VEGF delivery reversed the TAC-induced deficiencies in cardiac microvessel formation and ventricular function observed in the APN-KO mice. In cultured cardiac myocytes, adiponectin treatment stimulated VEGF production, which was inhibited by inactivation of AMPK signaling pathway. Collectively, these data show that adiponectin deficiency can accelerate the transition from cardiac hypertrophy to heart failure during pressure overload through disruption of AMPK-dependent angiogenic regulatory axis.     

Sacubitril/Valsartan Improves Left Ventricular Function in Chronic Pressure Overload Independent of Intact Cyclic Guanosine Monophosphate-dependent Protein Kinase I Alpha Signaling

BackgroundCombined angiotensin receptor/neprilysin inhibition with sacubitril/valsartan (Sac/Val) has emerged as a therapy for heart failure. The presumed mechanism of benefit is through prevention of natriuretic peptide degradation, leading to increased cyclic guanosine monophosphate (cGMP)-dependent protein kinase (PKG) signaling. However, the specific requirement of PKG for Sac/Val effects remains untested.Methods and ResultsWe examined Sac/Val treatment in mice with mutation of the cGMP-dependent protein kinase I (PKGI)α leucine zipper domain, which is required for cGMP-PKGIα antiremodeling actions in vivo. Wild-type (WT) or PKG leucine zipper mutant (LZM) mice were exposed to 56-day left ventricular (LV) pressure overload by moderate (26G) transaortic constriction (TAC). At day 14 after TAC, mice were randomized to vehicle or Sac/Val by oral gavage. TAC induced the same degree of LV pressure overload in WT and LZM mice, which was not affected by Sac/Val. Although LZM mice, but not WT, developed LV dilation after TAC, Sac/Val improved cardiac hypertrophy and LV fractional shortening to the same degree in both the WT and LZM TAC mice.ConclusionThese findings indicate the beneficial effects of Sac/Val on LV structure and function in moderate pressure overload. The unexpected finding that PKGIα mutation does not abolish the Sac/Val effects on cardiac hypertrophy and on LV function suggests that signaling other than natriuretic peptide– cGMP–PKG mediates the therapeutic benefits of neprilysin inhibition in heart failure.     

Enhanced Gαq signaling: A common pathway mediates cardiac hypertrophy and apoptotic heart failure

Receptor-mediated Gq signaling promotes hypertrophic growth of cultured neonatal rat cardiac myocytes and is postulated to transduce in vivo cardiac pressure overload hypertrophy. Although initially compensatory, hypertrophy can proceed by unknown mechanisms to cardiac failure. We used adenoviral infection and transgenic overexpression of the alpha subunit of Gq to autonomously activate Gq signaling in cardiomyocytes. In cultured cardiac myocytes, overexpression of wild-type Gαq resulted in hypertrophic growth. Strikingly, expression of a constitutively activated mutant of Gαq, which further increased Gq signaling, produced initial hypertrophy, which rapidly progressed to apoptotic cardiomyocyte death. This paradigm was recapitulated during pregnancy in Gαq overexpressing mice and in transgenic mice expressing high levels of wild-type Gαq. The consequence of cardiomyocyte apoptosis was a transition from compensated hypertrophy to a rapidly progressive and lethal cardiomyopathy. Progression from hypertrophy to apoptosis in vitro and in vivo was coincident with activation of p38 and Jun kinases. These data suggest a mechanism in which moderate levels of Gq signaling stimulate cardiac hypertrophy whereas high level Gq activation results in cardiomyocyte apoptosis. The identification of a single biochemical stimulus regulating cardiomyocyte growth and death suggests a plausible mechanism for the progression of compensated hypertrophy to decompensated heart failure.     

Deletion of angiotensin-converting enzyme 2 accelerates pressure overload-induced cardiac dysfunction by increasing local angiotensin II

Angiotensin-converting enzyme 2 (ACE2) is a carboxypeptidase that cleaves angiotensin II to angiotensin 1-7. Recently, it was reported that mice lacking ACE2 (ACE2(-/y) mice) exhibited reduced cardiac contractility. Because mechanical pressure overload activates the cardiac renin-angiotensin system, we used ACE2(-/y) mice to analyze the role of ACE2 in the response to pressure overload. Twelve-week-old ACE2(-/y) mice and wild-type (WT) mice received transverse aortic constriction (TAC) or sham operation. Sham-operated ACE2(-/y) mice exhibited normal cardiac function and had morphologically normal hearts. In response to TAC, ACE2(-/y) mice developed cardiac hypertrophy and dilatation. Furthermore, their hearts displayed decreased cardiac contractility and increased fetal cardiac gene induction, compared with WT mice. In response to chronic pressure overload, ACE2(-/y) mice developed pulmonary congestion and increased incidence of cardiac death compared with WT mice. On a biochemical level, cardiac angiotensin II concentration and activity of mitogen-activated protein (MAP) kinases were markedly increased in ACE2(-/y) mice in response to TAC. Administration of candesartan, an AT1 subtype angiotensin receptor blocker, attenuated the hypertrophic response and suppressed the activation of MAP kinases in ACE2(-/y) mice. Activation of MAP kinases in response to angiotensin II was greater in cardiomyocytes isolated from ACE2(-/y) mice than in those isolated from WT mice. ACE2 plays an important role in dampening the hypertrophic response to pressure overload mediated by angiotensin II. Disruption of this regulatory function may accelerate cardiac hypertrophy and shorten the transition period from compensated hypertrophy to cardiac failure.     

Thrombomodulin is upregulated in cardiomyocytes during cardiac hypertrophy and prevents the progression of contractile dysfunction

BackgroundCardiac hypertrophy is a common response to pressure overload and leads to left ventricular (LV) dysfunction. Thrombomodulin (TM), an endothelial anticoagulant protein, was found to have direct effects on cellular proliferation and inflammation. We examined the TM expression in cardiomyocytes during cardiac hypertrophy and investigated its physiological significance.Methods and ResultsTM expression was evaluated in cardiomyocytes from hearts of mice that underwent transverse aortic constriction (TAC). The effects of recombinant TM protein on cardiomyocytes apoptosis and related signaling pathways were examined. Recombinant TM protein was administered continuously in mice that underwent TAC, and serial LV function was determined. There was significant TM expression in cardiomyocytes during cardiac hypertrophy elicited by TAC in mice. TM treatment decreased doxorubicin-induced apoptosis of cardiomyocytes and increased the Bcl-2/Bax ratio. It also increased cardiomyocytes hypertrophy, expression of atrial natriuretic peptide, and significantly activated the extracellular signal–regulated kinase 1/2 (ERK1/2) and the phosphatidylinositol-3-kinase (PI3-K)/protein kinase B (Akt) signaling pathways in cardiomyocytes. Continuous TM supply after TAC prevented the progression of LV contractile dysfunction in mice.ConclusionsTM treatment decreased cardiomyocyte apoptosis and maintained LV contractile function in response to pressure overload.     

c-Flip overexpression reduces cardiac hypertrophy in response to pressure overload

OBJECTIVE: Activation of Fas signaling has been associated with the development of cardiomyocyte hypertrophy. In the present study, we investigated the effects of increased expression of c-Flip, a natural modulator of Fas receptor signaling, in a mouse model of cardiac growth response to pressure overload. METHODS: A transgenic mouse overexpressing c-Flip in the heart was generated in FVB/N strain. Echocardiographic, hemodynamic, histological and molecular analyses were carried out under basal conditions and after transverse aortic constriction (TAC)-induced pressure overload. RESULTS: Overexpression of c-Flip in ventricular heart tissue was functionally silent under basal conditions affecting neither cardiac morphology nor basal cardiac function. Transgenic mice were then subjected to pressure overload by TAC procedure. Under such conditions, c-Flip transgenic mice showed normal left ventricular function with a significantly reduced left ventricular hypertrophy compared with wild-type mice and reduced induction of the cardiac "fetal" gene programme. Further, analysis of intracellular signaling pathways indicated that c-Flip overexpression reduced phosphorylation of both the glycogen synthase kinase 3beta (GSK3 beta) and Akt as compared with controls. Finally, the reduction of the TAC-induced hypertrophy was not accompanied by significant apoptosis increase. CONCLUSION: Altogether, these findings indicate c-Flip as a key regulator of the cardiac response to ventricular pressure overload.     

奥美沙坦不依赖血管紧张素Ⅱ改善压力超负荷诱发的小鼠心脏肥大

目的探讨奥美沙坦在无内源性血管紧张素II(AngII)情况下能否抑制压力超负荷导致的小鼠心脏肥厚。方法通过缩窄升主动脉(TAC)构建小鼠压力超负荷心脏肥大模型。8-10周龄野生型(WT)和血管紧张素原基因敲除(ATGKO)小鼠各随机分为3组:假手术组,生理盐水组和奥美沙坦组。TAC两周后,对小鼠心脏进行超声及病理形态学检测,同时测量左心室压力、全心/体重比值以及相关肥大基因检测。结果相对于假手术组,生理盐水组心脏肥厚各项指标值明显变大(P0.05)。奥美沙坦组心脏肥厚的各项指标值均显著低于生理盐水组(P0.05);在WT小鼠和ATGKO小鼠可见相似结果。结论奥美沙坦在无内源性AngII的条件下也能有效抑制压力超负荷所致心肌肥厚,其作用机制可能是不依赖于AngII而直接抑制压力超负荷触发的AT1受体的活化。     

Targeted deletion of matrix metalloproteinase 2 ameliorates myocardial remodeling in mice with chronic pressure overload

Matrix metalloproteinases (MMPs) play an important role in the extracellular matrix remodeling. Experimental and clinical studies have demonstrated that MMP 2 and 9 are upregulated in the dilated failing hearts and involved in the development and progression of myocardial remodeling. However, little is known about the role of MMPs in mediating adverse myocardial remodeling in response to chronic pressure overload (PO). We, thus, hypothesized that selective disruption of the MMP 2 gene could ameliorate PO-induced cardiac hypertrophy and dysfunction in mice. PO hypertrophy was induced by transverse aortic constriction (TAC) in male MMP 2 knockout (KO) mice (n=10) and sibling wild-type (WT) mice (n=9). At 6 weeks, myocardial MMP 2 zymographic activity was 2.4-fold increased in WT+TAC, and this increase was not observed in KO+TAC, with no significant alterations in other MMPs (MMP 1, 3, 8, and 9) or tissue inhibitors of MMPs (1, 2, 3, and 4). TAC resulted in a significant increase in left ventricular (LV) weight and LV end-diastolic pressure (EDP) with preserved systolic function. KO+TAC mice exerted significantly lower LV weight/body weight (4.2+/-0.2 versus 5.0+/-0.2 mg/g; P<0.01), lung weight/body weight (4.9+/-0.2 versus 6.2+/-0.4 mg/g; P<0.01), and LV end-diastolic pressure (4+/-1 versus 10+/-2 mm Hg; P<0.05) than WT+TAC mice despite comparable aortic pressure. KO+TAC mice had less myocyte hypertrophy (cross-sectional area; 322+/-14 versus 392+/-14 microm2; P<0.01) and interstitial fibrosis (collagen volume fraction; 3.3+/-0.5 versus 8.2+/-1.0%; P<0.01) than WT+TAC mice. MMP 2 plays an important role in PO-induced LV hypertrophy and dysfunction. The inhibition of MMP 2 activation may, therefore, be a useful therapeutic strategy to manage hypertensive heart disease.     

Vascular endothelial growth factor blockade promotes the transition from compensatory cardiac hypertrophy to failure in response to pressure overload

Cardiac hypertrophy is associated with upregulation of vascular endothelial growth factor (VEGF) in the myocardium. Here, we evaluated the effects of a decoy VEGF receptor on heart morphology and function to a murine model of pressure overload hypertrophy. Mice were administered adenoviral vector encoding a decoy VEGF receptor (Ad-Flk), and their hearts were subjected to pressure overload by transverse aortic constriction (TAC). Treatment with Ad-Flk led to a net reduction in capillary density in hearts subjected to TAC. Ad-Flk also led to a reduction in TAC-induced cardiac hypertrophy and promoted left ventricle dilatation and a loss in contractile function. Treatment with Ad-Flk markedly increased myocardial fibrosis and collagen gene upregulation. In contrast, Ad-Flk had no effect on any of these parameters in sham-treated mice. Administration of a VEGF trap reagent diminished pressure overload cardiac hypertrophy and promoted the progression to heart failure but had no effect on sham-treated animals. These findings suggest that VEGF is required to maintain myocardial capillary density and that reductions in the vascular bed are associated with the transition from compensatory hypertrophy to failure.     

Endothelial expression of hypoxia-inducible factor 1 protects the murine heart and aorta from pressure overload by suppression of TGF-β signaling

Chronic systemic hypertension causes cardiac pressure overload leading to increased myocardial O(2) consumption. Hypoxia-inducible factor 1 (HIF-1) is a master regulator of O(2) homeostasis. Mouse embryos lacking expression of the O(2)-regulated HIF-1α subunit die at midgestation with severe cardiac malformations and vascular regression. Here we report that Hif1a(f/f);Tie2-Cre conditional knockout mice, which lack HIF-1α expression only in Tie2(+) lineage cells, develop normally, but when subjected to pressure overload induced by transaortic constriction (TAC), they manifest rapid cardiac decompensation, which is accompanied by excess cardiac fibrosis and myocardial hypertrophy, decreased myocardial capillary density, increased myocardial hypoxia and apoptosis, and increased TGF-β signaling through both canonical and noncanonical pathways that activate SMAD2/3 and ERK1/2, respectively, within endothelial cells of cardiac blood vessels. TAC also induces dilatation of the proximal aorta through enhanced TGF-β signaling in Hif1a(f/f);Tie2-Cre mice. Inhibition of TGF-β signaling by treatment with neutralizing antibody or pharmacologic inhibition of MEK-ERK signaling prevented TAC-induced contractile dysfunction and pathological remodeling. Thus, HIF-1 plays a critical protective role in the adaptation of the heart and aorta to pressure overload by negatively regulating TGF-β signaling in endothelial cells. Treatment of wild-type mice with digoxin, which inhibits HIF-1α synthesis, resulted in rapid cardiac failure after TAC. Although digoxin has been used for decades as an inotropic agent to treat heart failure, it does not improve survival, suggesting that the countertherapeutic effects of digoxin observed in the TAC mouse model may have clinical relevance.     

Inhibition of protein phosphatase 1 by inhibitor-2 exacerbates progression of cardiac failure in a model with pressure overload

AIMS: The progression of human heart failure is associated with increased protein phosphatase 1 (PP1) activity, which leads to a higher dephosphorylation of cardiac regulatory proteins such as phospholamban. In this study, we tested the hypothesis whether the inhibitor-2 (I-2) of PP1 can mediate cardiac protection by inhibition of PP1 activity. METHODS AND RESULTS: We induced pressure overload by transverse aortic constriction (TAC) for 28 days in transgenic (TG) mice with heart-directed overexpression of a constitutively active form of I-2 (TG(TAC)) and wild-type littermates (WT(TAC)). Both groups were compared with sham-operated mice. TAC treatment resulted in comparable ventricular hypertrophy in both groups. However, TG(TAC) exhibited a higher atrial mass and an enhanced ventricular mRNA expression of beta-myosin heavy chain. The increased afterload was associated with the development of focal fibrosis in TG. Consistent with signs of overt heart failure, fractional shortening and diastolic function were impaired in TG(TAC) as revealed by Doppler echocardiography. The contractility was reduced in catheterized banded TG mice, which is in line with a depressed shortening of isolated myocytes. This is due to profoundly abnormal cytosolic Ca(2+) transients and a reduced stimulation of phosphorylation of phospholamban (PLB)(Ser16) after TAC in TG mice. Moreover, administration of isoproterenol was followed by a blunted contractile response in isolated myocytes of TG(TAC) mice. CONCLUSION: These results suggest that cardiac-specific overexpression of a constitutively active form of I-2 is deleterious for cardiac function under conditions of pressure overload. Thus, the long-term inhibition of PP1 by I-2 is not a therapeutic option in the treatment of heart failure.     

Altered calcium transient and development of hypertrophy in beta2-adrenoceptor overexpressing mice with and without pressure overload

Transgenic (TG) mice with cardiac specific 200-fold overexpression of beta(2)-adrenoceptors (beta(2)-AR) have a facilitated development of heart failure following thoracic aortic constriction (TAC). We have studied the alterations of intracellular Ca(2+) transients and myocyte size in wild-type (WT) and TG mice after TAC. Cardiomyocytes were isolated from mice 9 weeks after TAC or sham operation, and incubated with Fura 2/AM. The Ca(2+) transients were determined by Spex dual wavelength Spectrometer during electrical stimulation. The cell size was also determined planimetrically. Cells of sham operated TG mice displayed higher systolic Ca(2+) amplitude than respective WT group (DeltaF(340)/F(380) ratio: 1.05+/-0.08 vs. 0.63+/-0.05; P<0.01), a finding in keeping with enhanced ventricular contractility in the TG mice. However, hypertrophied and failing myocytes of TG animals showed a fall in Ca(2+) transients from sham-operated control levels and there was no difference between TG and WT groups following TAC. In sham-operated groups, the cell size of TG mice was significantly bigger than in WT animals (3212+/-139 vs. 2605+/-162 microm(2); P<0.05). The cell size increased to a similar extent in both groups after TAC (4715+/-216 vs. 5027+/-365 microm(2), P=n.s.). In summary, hypertrophy of cardiomyocytes was present in beta(2)-AR TG mice under baseline conditions. A further hypertrophy occurred during pressure overload to an extent similar to that in WT animals. However, the increased intracellular Ca(2+) transient, seen in sham-operated TG mice, was no longer detectable following development of severe hypertrophy and heart failure. These findings provide explanation on the lack of hemodynamic benefit in beta(2)-AR TG mice subjected to pressure overload.     

Exacerbation of heart failure in adiponectin-deficient mice due to impaired regulation of AMPK and glucose metabolism

OBJECTIVE: Insulin resistance (IR) was reported to be associated with chronic heart failure (CHF). Adiponectin, an insulin-sensitizing hormone with anti-inflammatory activity, improves energy metabolism via AMP-activated protein kinase (AMPK). AMPK deficiency is associated with depressed cardiac function under stress conditions. However, it is not clear whether adiponectin plays an important role in CHF. We hypothesize that deficiency of adiponectin might result in deterioration of heart failure. METHODS: Using adiponectin null mice and their littermates, we examined the effects of adiponectin on LV pressure overload-induced cardiac hypertrophy and failure, and investigated the mechanisms involved. RESULTS: Three weeks after transverse aortic constriction (TAC), cardiac hypertrophy (evaluated from the heart-to-body weight ratio: 7.62+/-0.27 in wild-type (WT) mice, 9.97+/-1.13 in knockout (KO) mice, P<0.05) and pulmonary congestion (lung-to-body weight ratio: 9.05+/-1.49 in WT mice, 14.95+/-2.36 in KO mice, P<0.05) were significantly greater in adiponectin KO mice than WT mice. LV dimensions were also increased in KO mice. Compared with WT TAC mice, expression of AMPKalpha protein was lower, while IR was higher in KO TAC mice. CONCLUSION: These findings indicate that adiponectin deficiency leads to progressive cardiac remodeling in pressure overloaded condition mediated via lowing AMPK signaling and impaired glucose metabolism.     

氯沙坦对压力超负荷小鼠心肌肥厚和高迁移率族蛋白B1表达的影响

目的探讨氯沙坦对压力超负荷小鼠心肌肥厚和高迁移率族蛋白B1(HMGB1)表达的影响及机制。方法采用主动脉弓缩窄(TAC)方法建立压力超负荷小鼠心肌肥厚模型,并将小鼠随机分为假手术组、TAC+生理盐水组、TAC+氯沙坦组。术后2周行心脏超声检测并分析心肌组织学变化。同时,检测小鼠血清和心肌组织中HMGB1基因和蛋白表达水平,并检测心肌组织中细胞外信号调节激酶(ERK1/2)、P38和核转录因子(NF-κB)的表达及活化水平。结果TAC小鼠术后2周出现心肌肥厚,且氯沙坦可有效改善由TAC导致的左心室室壁增厚(P<0.05)。同时,TAC不仅升高小鼠血清HMGB1水平(P<0.05),还增加心肌HMGB1 mRNA和蛋白表达(P<0.05),而这些变化都可以被氯沙坦部分抑制(P<0.05)。此外,TAC导致心肌组织中p-ERK1/2、p-P38、p-NF-κB水平明显升高(P<0.05),且同样可以被氯沙坦部分抑制(P<0.05)。结论氯沙坦在改善压力超负荷所致心肌肥厚时伴随HMGB1表达减少,该作用可能与其阻断丝裂原活化蛋白激酶家族(MAPKs)及NF-κB信号通路有关。