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PubMed1996

Sarcoplasmic reticulum genes are upregulated in mild cardiac hypertrophy but downregulated in severe cardiac hypertrophy induced by pressure overload.

Changes in contractile and relaxation properties of heart muscle in the cardiac hypertrophy induced by pressure overload have been attributed to alterations in intracellular Ca2+ transport as well as the phenotypic and quantitative changes in contractile protein. However, contradictory data have been reported regarding Ca2+ uptake, release and storage by the sarcoplasmic reticulum (SR). The purpose of this study was to evaluate the changes in SR Ca(2+)-ATPase, ryanodine receptor, calsequestrin and alpha-actin gene expression, and the changes in Ca2+ uptake capacity in various degrees of hypertrophied hearts due to pressure overload. Cardiac hypertrophy was produced in rats by placing a constricting clip (0.80 mm) around the suprarenal abdominal aorta for 8 days. The mRNA levels and Ca2+ uptake capacity were then measured as a function of the severity of cardiac hypertrophy. Ca(2+)-ATPase and ryanodine receptor mRNA levels were increased in mildly hypertrophied hearts but were diminished in severely hypertrophied hearts, showing a bimodal response to pressure overload, Ca2+ uptake capacity showed similar changes along with a positive correlation with Ca(2+)-ATPase mRNA level (r = 0.67, P < 0.001). In contrast, the level of calsequestrin mRNA expression was unaltered and that of alpha-actin was markedly increased over a range of severity of cardiac hypertrophy. These findings suggest that the expression of sarcoplasmic reticulum genes for Ca2+ uptake and release is up- or downregulated dependent on the degree of pressure overload. The gene for the SR Ca2+ storage protein, calsequestrin, might be under different control from these genes in pressure overload. Our findings suggest that the decrease in ratio of mRNAs encoding Ca2+ uptake and release proteins to those encoding contractile proteins could significantly contribute to the slowed contractile and relaxation properties seen in pressure-overloaded hearts.

Actins↗
PubMed1991

Specific alterations in the distribution of extracellular matrix components within rat myocardium during the development of pressure overload.

Cardiac hypertrophy secondary to a sudden aortic pressure overload results in the remodeling of myocytes and extracellular matrix components. Hydroxyproline quantitation to evaluate total collagen content and immunocytochemistry procedures were used to analyze the temporal appearance and regional distribution of collagen, laminin, and fibronectin during the early stages of pressure overload. The study was performed in 25-day-old rats submitted to a thoracic aortic stenosis and killed from 1 day to 18 days after surgery. Cardiac hypertrophy reached 24.5% by day 2 and 75.5% by day 15. Each extracellular matrix component showed a unique distribution throughout the myocardium: in normal hearts, type I/III collagens appeared mainly as large strands or waves around groups of myocytes, fibronectin predominated around small and large vessels, while laminin surrounded both myocytes and capillaries. As early as 2 days after surgery, fibronectin and type I/III collagens, but not laminin, accumulated in focal areas. Thereafter, these areas increased in size and number within the inner part of the left ventricle, and progressively affected the whole left ventricle. Fibronectin accumulation preceded that of collagen and occupied larger areas. The measure of hydroxyproline content demonstrated that during the 1st week after surgery the increase in collagen content is correlated with the increase in heart weight. In conclusion, the three components of the extracellular matrix studied here develop a specific pattern of accumulation in response to a sudden pressure overload that induces cardiac hypertrophy. Both fibronectin and collagen changes participate in the healing of focal myocardial necrosis secondary to the increased hemodynamic work and fibronectin appeared as a more sensitive marker of the cardiac lesions than collagen.

Animals↗
PubMed1998

Decompensation of pressure-overload hypertrophy in G alpha q-overexpressing mice.

BACKGROUND: Receptor-mediated activation of myocardial Gq signaling is postulated as a biochemical mechanism transducing pressure-overload hypertrophy. The specific effects of Gq activation on the functional and morphological adaptations to pressure overload are not known. METHODS AND RESULTS: To determine the effects of intrinsic myocyte G alpha q signaling on the left ventricular hypertrophic response to experimental pressure overload, transgenic mice overexpressing G alpha q specifically in the heart (G alpha q-25) and nontransgenic siblings underwent microsurgical creation of transverse aortic coarctation and the morphometric, functional, and molecular characteristics of these pressure-overloaded hearts were compared at increasing times after surgery. Before aortic banding, isolated G alpha q-25 ventricular myocytes exhibited contractile depression (depressed +dl/dt and -dl/dt) and G alpha q-25 hearts showed a pattern of fetal gene expression similar to the known characteristics of nontransgenic pressure-overloaded mice. Three weeks after transverse aortic banding, G alpha q-25 left ventricles hypertrophied to a similar extent (approximately 30% increase) as nontransgenic mice. However, whereas nontransgenic mice exhibited concentric left ventricular remodeling with maintained ejection performance (compensated hypertrophy), G alpha q-25 left ventricles developed eccentric hypertrophy and ejection performance deteriorated, ultimately resulting in left heart failure (decompensated hypertrophy). The signature hypertrophy-associated progress of fetal cardiac gene expression observed at baseline in G alpha q-25 developed after aortic banding of nontransgenic mice but did not significantly change in aortic-banded G alpha q-25 mice. CONCLUSIONS: Intrinsic cardiac myocyte G alpha q activation stimulates fetal gene expression and depresses cardiac myocyte contractility. Superimposition of the hemodynamic stress of pressure overload on G alpha q overexpression stimulates a maladaptive form of eccentric hypertrophy that leads to rapid functional decompensation. Therefore G alpha q-stimulated cardiac hypertrophy is functionally deleterious and compromises the ability of the heart to adapt to increased mechanical load. This finding supports a reevaluation of accepted concepts regarding the mechanisms for compensation and decompensation in pressure-overload hypertrophy.

Animals↗
PubMed1984

[Echocardiographic study of right ventricular performance by acute and chronic pressure overloadings].

Echocardiographic analysis of right ventricular ejection time (RVET), pre-ejection time (RVPEP), RVPEP/ET and isovolumic relaxation time (RVIRT) was performed in patients with acute or chronic right ventricular pressure overloading. Fifty-five patients undergoing right ventricular cardiac catheterization, were categorized into seven groups; 11 patients with atrial septal defect (ASD) without pulmonary hypertension (PH) (group 1), 12 with ASD with PH (group 2), six with mitral stenosis (MS) without PH (group 3), nine with MS with PH (group 4), seven with primary pulmonary hypertension (PPH) (group 5), seven with acute pulmonary embolism (PE) (group 6), and three patients with convalescence of PE (group 7). Corrected RVIRT (RVIRTc) and RVET (RVETc) were calculated by regression analysis correlating with heart rate in normal subjects. RVIRTc, RVETc, RVPEP and RVPEP/ET in seven groups were significantly correlated with systolic pulmonary artery pressure (SPAP) (r = 0.62, p less than 0.001; r = -0.41, p less than 0.01; r = 0.61, p less than 0.001; r = 0.65, p less than 0.001, respectively), but RVDd did not correlate with SPAP (r = 0.370, p less than 0.05). Comparing acute right ventricular pressure overloading group (group 6) with each of chronic right ventricular pressure overloading groups (groups 2, 4, 5, and 7), RVIRTc and RVDd were significantly increased in the former than the latter, but RVETc, RVPEP and RVPEP/ET were not significantly different in both groups. There was a significant correlation between RVIRTc and RVPEP/ET in chronic pressure overloading, but not in acute pressure overloading. We concluded that early diastolic RV relaxation and systolic performance were both impaired by increased afterload in chronic pressure overloading. In acute pressure overloading, however, early diastolic RV relaxation was more significantly impaired possibly because of acute changes of muscle architectures due to acute right ventricular expansion and anoxia.

Blood Pressure↗
PubMed1992

Energetics of acute pressure overload of the porcine right ventricle. In vivo 31P nuclear magnetic resonance.

In vivo 31P nuclear magnetic resonance (NMR) spectroscopy of the right ventricular (RV) free wall was employed to determine (a) whether phosphorus energy metabolites vary reciprocally with workload in the RV and (b) the mechanisms that limit RV contractile function in acute pressure overload. In 20 open-chest pigs, phosphocreatine (PCr)/ATP ratio (an index of energy metabolism inversely related to free ADP concentration), myocardial blood flow (microspheres), and segment shortening (sonomicrometry, n = 14) were measured at control (RV systolic pressure 31 +/- 1 mm Hg), and with pulmonary artery constriction to produce moderate pressure overload (RV systolic pressure 45 +/- 1 mm Hg), and maximal pressure overload before overt RV failure and systemic hypotension (RV systolic pressure 60 +/- 1 mm Hg). With moderate pressure overload, PCr/ATP declined to 89% of control (P = 0.01), while contractile function increased. Adenosine (n = 10, mean dose 0.16 mg/kg-min) increased RV blood flow by an additional 41% without increasing PCr/ATP, indicating that coronary reserve was not depleted and that the decrease in PCr/ATP from control was not due to ischemia. With maximal pressure overload and incipient RV failure, PCr/ATP fell further to 81% of control and RV blood flow did not increase further, even with adenosine. Thus: (a) The decline in PCr/ATP with moderate RV pressure overload, without evident ischemia or contractile dysfunction, supports the positive regulation of oxidative phosphorylation by ATP hydrolysis products. (b) Depletion of RV coronary flow reserve accompanies the onset of RV failure at maximal pressure overload.

Adenosine Triphosphate↗
PubMed1989

Functional and geometrical interference and interdependency between the right and left ventricle in cor pulmonale: an experimental study on simultaneous measurement of biventricular geometry of acute right ventricular pressure overload.

To clarify the effects of right ventricular (RV) pressure overload on functional and geometrical interference and interdependency between the right and left ventricle, both ventricular internal diameters were measured by the microcrystal technique during lycopodium induced pulmonary embolization in the dog. By repeated embolization, RV systolic pressure was increased progressively until it reached a peak value of about 60-70 mmHg, then it began to fall. At the same time, the hemodynamics deteriorated progressively resulting in death. During the experiment, gradual leftward displacement of the interventricular septum (IVS) without any change in left ventricular (LV) free wall geometry was observed. In pulmonary embolic shock, which showed a fall in LV pressure to about 60 mmHg and cardiac output to about 40% of control, the leftward displacement of IVS became marked, and the cooperative movement of IVS to LV contraction disappeared. The IVS position during acute RV pressure overload was able to account for the transseptal pressure gradient. The importance of IVS position and motion in cardiac function during acute RV pressure overload was stressed. Furthermore, to establish the theoretical treatment in acute cardiopulmonary resuscitation, ligation of the descending aorta (AoL) or norepinephrine ("N") or isoproterenol ("I") administration were examined in a canine pulmonary embolic shock model. AoL or "N" improved the deteriorated hemodynamics with restoration of biventricular geometry. However, "I" did not restore the biventricular geometry despite the transiently improved hemodynamics, and the experimental animals were unable to survive. These results suggest the importance of the maintainance of systemic pressure for the restoration of failed RV function. Further integrated studies are required to understand biventricular interference and interdependency.

Animals↗
PubMed1987

Cellular electrophysiology of coronary artery ligation in chronic pressure overload.

We evaluated ischemia-induced cellular electrophysiologic abnormalities in chronic pressure overload ventricular myocardium in vitro. Left ventricular systolic hypertension was induced in cats via partial supracoronary aortic constriction (overload); at 1 1/2-3 months, resulting pressure overload was accompanied by ventricular hypertrophy (25-35% by weight) and patchy endocardial fibrosis. Two hours of subsequent acute myocardial ischemia (ischemia) was imposed on overload (ischemia/overload) via total occlusion of distal branches of the left coronary artery system. Spontaneous premature depolarizations in vitro were increased in ischemia/overload compared to control, ischemia or overload alone; bursts of spontaneous, repetitive depolarizations were also unique to these preparations. Multiple site recordings of endocardial transmembrane action potentials overlying the borders (interface) of fibrotic areas in ischemia/overload demonstrated numerous electrophysiologic abnormalities, including several not observed in control, ischemia or overload. Unique to the border areas of ischemia/overload preparations was the presence of maintained but depressed resting potential without action potentials; also, the incidence of depolarizations at the onset of the plateau phase was highest in these preparations. In non-fibrotic areas, electrophysiologic properties including resting potential and action potential amplitude and rate of rise were diminished in ischemia/overload compared to ischemia or overload preparations. These data demonstrate that acute myocardial ischemia in the setting of chronic pressure overload leads to additional cellular electrophysiologic abnormalities compared to ischemia or overload alone.

Action Potentials↗
PubMed2005

Cardiac overexpression of melusin protects from dilated cardiomyopathy due to long-standing pressure overload.

We have previously shown that genetic ablation of melusin, a muscle specific beta 1 integrin interacting protein, accelerates left ventricle (LV) dilation and heart failure in response to pressure overload. Here we show that melusin expression was increased during compensated cardiac hypertrophy in mice subjected to 1 week pressure overload, but returned to basal levels in LV that have undergone dilation after 12 weeks of pressure overload. To better understand the role of melusin in cardiac remodeling, we overexpressed melusin in heart of transgenic mice. Echocardiography analysis indicated that melusin over-expression induced a mild cardiac hypertrophy in basal conditions (30% increase in interventricular septum thickness) with no obvious structural and functional alterations. After prolonged pressure overload (12 weeks), melusin overexpressing hearts underwent further hypertrophy retaining concentric LV remodeling and full contractile function, whereas wild-type LV showed pronounced chamber dilation with an impaired contractility. Analysis of signaling pathways indicated that melusin overexpression induced increased basal phosphorylation of GSK3beta and ERK1/2. Moreover, AKT, GSK3beta and ERK1/2 were hyper-phosphorylated on pressure overload in melusin overexpressing compared with wild-type mice. In addition, after 12 weeks of pressure overload LV of melusin overexpressing mice showed a very low level of cardiomyocyte apoptosis and stromal tissue deposition, as well as increased capillary density compared with wild-type. These results demonstrate that melusin overexpression allows prolonged concentric compensatory hypertrophy and protects against the transition toward cardiac dilation and failure in response to long-standing pressure overload.

Animals↗
PubMed1987

Myocardial changes during the progression of left ventricular pressure-overload by renal hypertension or aortic constriction: myosin, myosin ATPase and collagen.

We measured the interrelationships between ventricular muscle myosin mass, myosin ATPase activity and collagen in cats with varying degrees of hypertrophy from left ventricular (LV) pressure-overload produced by either aortic banding or renal hypertension. In order to compare two models of LV pressure-overload with different time courses of progression, the results were analyzed as a function of LV mass or LV weight/body weight (LV/BW) ratio. Myosin was quantitated by SDS-polyacrylamide gel electrophoresis and hydroxyproline was measured as an index of collagen. Myosin concentration was positively correlated with increasing LV mass in control cats. However, in pressure-overloaded LV, myosin concentration was elevated and nearly constant for LV less than 9.0 g, but decreased in LV greater than 9.0 g. Myosin concentration in pressure-overloaded LV was greatest before a significant increase in LV/BW ratio. Hydroxyproline concentration was inversely related to myosin concentration in both LV pressure-overload models and increased with the severity of hypertrophy. Actomyosin ATPase activity in pressure-overloaded LV, was not significantly different from control over a wide range of LV/BW ratios. However, absolute myosin ATP hydrolysis in pressure-overloaded LV, increased by as much as 40%, relative to control, due primarily to increased myosin. The changing spectrum and interrelationships of myosin and collagen were independent of the mechanism of pressure-overload, but were correlated with the severity of hypertrophy.

Adenosine Triphosphatases↗
PubMed1999

Transcription of the SERCA2 gene is decreased in pressure-overloaded hearts: A study using in vivo direct gene transfer into living myocardium.

T. Takizawa, M. Arai, A. Yoguchi, K. Tomaru, M. Kurabayashi and R. Nagai. Transcription of the SERCA2 Gene is Decreased in Pressure-overloaded Hearts: A Study Using In Vivo Direct Gene Transfer into Living Myocardium. Journal of Molecular and Cellular Cardiology (1999) 31, 2167-2174. The sarcoplasmic reticulum Ca(2+)-ATPase (SERCA2) controls the myocardial relaxation process. Under pressure-overload, the expression of its mRNA decreases, thus controlling cardiac function to conform to the load. However, it is not known whether this decreased expression is caused by a decrease in the transcription of the SERCA2 gene. The object of this study was to determine the transcription control mechanism of the SERCA2 gene under pressure-overload in vivo, and to identify the pressure-overload-sensitive regions of the SERCA2 gene. Ten micrograms of a plasmid, containing the 5' upstream (-1810 bp to +350 bp) region of the SERCA2 gene and a luciferase reporter gene, were introduced into adult rat myocardium by in vivo direct gene transfer, and the luciferase activity was measured 5 days later. The transcriptional activity under pressure-overload decreased to 27+/-17% of the control. Based on this result, we concluded that the decreased mRNA expression of SERCA2 in pressure-overload cardiac hypertrophy is due to decreased gene transcription. In addition, various deletion fragments of the SERCA2 promoter region were produced, and tested for luciferase production under pressure-overload. Our data suggest that a transcription activation site is present between -685 and -284 bp, and two transcription inhibition sites are present between -1810 to -1110 bp and -284 to -72 bp. These may be the pressure-sensitive regions of the SERCA2 gene of in vivo hypertrophied myocardium under pressure-overload.

Animals↗
PubMed1996

[Expression of c-fos mRNA induced by pressure overload in the left ventricle].

In the present study the effect of pressure overload on the expression of protooncogene c-fos in the left ventricle was investigated in rats with abdominal aorta constriction. It was found that a remarkable expression of c-fos was induced by pressure overload and the expression was greatly attenuated by angiotensin converting enzyme inhibitor captopril. In the pressure overload group the angiotensinogen mRNA level was found increased. The above results suggest that angiotensin II is involved in the expression of c-fos due to pressure overload.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2001

Antiadrenergic effects of adenosine in pressure overload hypertrophy.

In the present study, we sought to evaluate whether the antiadrenergic action of adenosine in the heart is altered in pressure overload hypertrophy produced in rats by suprarenal aortic banding. Epicardial and coronary effluent adenosine and inosine concentrations and release were significantly elevated in compensated pressure overload hypertrophy but not in hearts with left ventricular failure. In pressure overload hearts, the contractile response to beta-adrenergic stimulation was less inhibited by incremental concentrations of either adenosine or the selective A(1) receptor agonist chloro-N:(6)-cyclopentyl adenosine than in controls. Furthermore, the extent of desensitization to the antiadrenergic actions of adenosine in pressure overload hypertrophy appeared to be proportional to the extent of chamber dilation and dysfunction. A 60-minute infusion of adenosine produced a sustained antiadrenergic effect that lasted up to 45 minutes after the infusion was terminated in both controls and hearts with compensated hypertrophy. This effect was not observed in the decompensated left ventricular failure group. Subsequent infusion with adenosine of the A(2A) receptor antagonist 8-(3-chlorostyryl)-caffeine to counteract the proadrenergic effect of A(2A) receptor stimulation did not alter the decreased sensitivity to the antiadrenergic actions of adenosine in hypertrophied hearts. Finally, isolated myocytes from hypertrophied hearts demonstrated a decreased ability to suppress isoproterenol-elicited increases in [Ca(2+)](i) transients in the presence of adenosine and the A(2A) receptor antagonist compared with myocytes from control hearts. Myocardial adenosine concentrations increase during the compensated phase of pressure overload hypertrophy but then decrease when there is evidence of decompensation. The antiadrenergic actions of adenosine transduced via the myocardial A(1) receptor are diminished in pressure overload hypertrophied hearts. These factors may render these hearts more vulnerable to the detrimental effects of chronically increased sympathetic activity.

Adenosine↗
PubMed2003

Minimally invasive aortic banding in mice: effects of altered cardiomyocyte insulin signaling during pressure overload.

We developed a minimally invasive method for producing left ventricular (LV) pressure overload in mice. With the use of this technique, we quickly and reproducibly banded the transverse aorta with low surgical morbidity and mortality. Minimally invasive transverse aortic banding (MTAB) acutely and chronically increased LV systolic pressure, increased heart weight-to-body weight ratio, and induced myocardial fibrosis. We used this technique to determine whether reduced insulin signaling in the heart altered the cardiac response to pressure overload. Mice with cardiac myocyte-restricted knockout of the insulin receptor (CIRKO) have smaller hearts than wild-type (WT) controls. Four weeks after MTAB, WT and CIRKO mice had comparably increased LV systolic pressure, increased cardiac mass, and induction of mRNA for beta-myosin heavy chain and atrial natriuretic factor. However, CIRKO hearts were more dilated, had depressed LV systolic function by echocardiography, and had greater interstitial fibrosis than WT mice. Expression of connective tissue growth factor was increased in banded CIRKO hearts compared with WT hearts. Thus lack of insulin signaling in the heart accelerates the transition to a more decompensated state during cardiac pressure overload. The use of the MTAB approach should facilitate the study of the pathophysiology and treatment of pressure-overload hypertrophy.

Animals↗
PubMed1984

Left ventricular function of concentric hypertrophied heart after chronic pressure overload as studied in the isolated canine heart preparation.

The function of the pressure-overload left ventricle was studied in relation to the chamber geometry of the isolated canine heart. The occurrence of concentric hypertrophy was confirmed in dogs with aortic constriction 40 weeks after operation. The effect of the concentric hypertrophy on left ventricular function was then studied in five pressure-overload dogs. The end-diastolic pressure of the preparation was preset at 20 mmHg. In the pressure-overload ventricle, the end-diastolic volume was smaller by 47% (p less than 0.01) and the peak systolic pressure was higher by 24% (p less than 0.01) than the control at isovolumic beats. Ejection pressure was controlled by our afterload controlling system at various levels and kept constant during the ejection phase. When ejection pressure was the same, the difference in stroke volume between the experimental and control groups was not significant. In the pressure-overload ventricle, the slope (the reciprocal is Emax) of the regression line of the end-systolic volume on ejection pressure decreased (p less than 0.01) to 0.095 ml/mmHg by 47% from 0.186 ml/mmHg in the control. The volume-axis intercept (Vd) of the line was reduced to 55% of the control. A decrease in the regression line slope was in linear proportion to the degree of concentric hypertrophy, namely, to the change in chamber geometry. These results indicated that: Despite reduction of the end-diastolic volume, the concentric hypertrophied ventricle showed no reduction in stroke volume at the same level of ejection pressure, because of its improved capability to generate pressure. Emax was dependent on ventricular geometry.

Animals↗
PubMed1996

Effects of long-term hydralazine treatment on myocardial structure and expression of myosin isogenes in cardiac pressure overload in rats.

The long-term effects of an arterial vasodilator, hydralazine, on myocardial structure and cardiac myosin isogene expression in pressure overload in rats were investigated. Portan rats were subjected to pressure overload by partial abdominal aortic constriction in order to study the effects of a 4-week treatment with hydralazine (15 mg/kg p.o.) on hemodynamics, ventricular structure, and ventricular total RNA, DNA, protein and myosin isoform expression pattern in sham (SO) and pressure-overloaded (p.o.) rats. P.o. increased the mean arterial pressure (MAP) and systolic blood pressure (SBP) and resulted in increased ventricular weight, LV wall thickness, total RNA and protein content; however, total DNA remained unchanged. The expression of fetal isogene beta-myosin heavy chain (beta-MHC) was markedly enhanced, whereas alpha-MHC was reduced. Hydralazine (15 mg/kg p.o.) normalized MAP and SBP, but did not modulate the hypertrophic changes of pressure-overloaded myocardium. It did not prevent an increase in ventricular total RNA and protein content and antithetical expression of myosin isoforms. Overall growth rate of rats was unaffected by hydralazine treatment. These results suggest that hydralazine has no direct effect in preventing the progression of cardiac hypertrophy and expression of beta-MHC, in spite of lowering blood pressure in pressure-overloaded rats. Thus, it further reaffirms that factors other than hemodynamics may play a pivotal role in the development of cardiac hypertrophy and induction of fetal isogene expression.

Analysis of Variance↗
PubMed2002

The MEKK1-JNK pathway plays a protective role in pressure overload but does not mediate cardiac hypertrophy.

Mitogen-activated protein kinase kinase kinase (MEKK1) mediates activation of c-Jun NH(2)-terminal kinase (JNK). Although previous studies using cultured cardiac myocytes have suggested that the MEKK1-JNK pathway plays a key role in hypertrophy and apoptosis, its effects in cardiac hypertrophy and apoptosis are not fully understood in adult animals in vivo. We examined the role of the MEKK1-JNK pathway in pressure-overloaded hearts by using mice deficient in MEKK1. We found that transverse aortic banding significantly increased JNK activity in Mekk1(+/+) but not Mekk1(-/-) mice, indicating that MEKK1 mediates JNK activation by pressure overload. Nevertheless, pressure overload caused significant levels of cardiac hypertrophy and expression of atrial natriuretic factor in Mekk1(-/-) animals, which showed higher mortality and lung/body weight ratio than were seen in controls. Fourteen days after banding, Mekk1(-/-) hearts were dilated, and their left ventricular ejection fraction was low. Pressure overload caused elevated levels of apoptosis and inflammatory lesions in these mice and produced a smaller increase in TGF-beta and TNF-alpha expression than occurred in wild-type controls. Thus, MEKK1 appears to be required for pressure overload-induced JNK activation and cytokine upregulation but to be dispensable for pressure overload-induced cardiac hypertrophy. MEKK1 also prevents apoptosis and inflammation, thereby protecting against heart failure and sudden death following cardiac pressure overload.

Animals↗
PubMed1997

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

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

Angiotensin II↗
PubMed2000

[Relation between myocardial cAMP and renin-angiotensin system activation after acute pressure overload].

In order to investigate the relationship between cAMP and myocardial renin-angiotensin system activation after acute pressure overload, an animal model of acute pressure overload was established by constriction of abdominal aorta. It was found that angiotensin converting enzyme (ACE) mRNA and protein expression were increased markedly, ACE activity and angiotensin II content were also elevated significantly in rat heart 1 h after acute pressure overload, and the increases were kept at high level. Meanwhile the myocardial cAMP concentration was increased significantly at 0.5 h, reached the peak at day 5, and returned to normal at day 30 after operation. Then cardiomyocytes were cultured to observe whether ACE gene expression can be induced by cAMP. The results showed that elevation of cAMP content in cultured cardiomyocytes stimulated by isoproterenol (ISO, 0.01 micromol/L) increased ACE mRNA and protein expression, and also increased ACE activity and Ang II content in cultural medium. These results suggest that cAMP plays a role in the mechanism of activation of myocardial renin-angiotensin system induced by pressure overload.

Animals↗