Pressure Overload Stress Research Articles

Suppressor of cytokine signaling-3 is a biomechanical stress–inducible gene that suppresses gp130-mediated cardiac myocyte hypertrophy and survival pathways

The gp130 cytokine receptor activates a cardiomyocyte survival pathway during the transition to heart failure following the biomechanical stress of pressure overload. Although gp130 activation is observed transiently during transverse aortic constriction (TAC), its mechanism of inactivation is largely unknown in cardiomyocytes. We show here that suppressor of cytokine signaling 3 (SOCS3), an intrinsic inhibitor of JAK, shows biphasic induction in response to TAC. The induction of SOCS3 was closely correlated with STAT3 phosphorylation, as well as the activation of an embryonic gene program, suggesting that cardiac gp130-JAK signaling is precisely controlled by this endogenous suppressor. In addition to its cytoprotective action, gp130-dependent signaling induces cardiomyocyte hypertrophy. Adenovirus-mediated gene transfer of SOCS3 to ventricular cardiomyocytes completely suppressed both hypertrophy and antiapoptotic phenotypes induced by leukemia inhibitory factor (LIF). To our knowledge, this is the first clear evidence that these two separate cardiomyocyte phenotypes induced by gp130 activation lie downstream of JAK. Three independent signaling pathways, STAT3, MEK1-ERK1/2, and AKT activation, that are coinduced by LIF stimulation were completely suppressed by SOCS3 overexpression. We conclude that SOCS3 is a mechanical stress–inducible gene in cardiac muscle cells and that it directly modulates stress-induced gp130 cytokine receptor signaling as the key molecular switch for a negative feedback circuit for both myocyte hypertrophy and survival.

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

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. 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. 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.

Carvedilol, a novel vasodilating beta-blocker with the potential for cardiovascular organ protection

Carvedilol is a vasodilating beta-blocker currently marketed for the treatment of mild to moderate hypertension and application is being filed to the FDA for treatment of congestive heart failure. Carvedilol reduces peripheral vascular resistance by blocking arterial alpha 1-adrenoceptors, thereby producing vasodilation, while preventing reflex tachycardia by blocking cardiac beta 1- and beta 2-adrenoceptors. In addition to the safety and efficacy of carvedilol as an antihypertensive agent, experimental studies indicate that carvedilol also provides significant cardioprotection in animal models of acute myocardial infarction as well as protection against the vascular remodelling that occurs following injury of the vasculature. Recent pharmacological studies have uncovered several novel properties of carvedilol which may function to protect the heart and vasculature from chronic pathological processes, such as ischaemia, atherosclerosis and the remodelling that occurs in the heart and blood vessels as a consequence of pressure overload, injury or shear stress. Specifically, carvedilol, likely as a result of the carbazol moiety, is a potent anti-oxidant. In physicochemical, biochemical and cellular assays carvedilol and several of its metabolites inhibit lipid peroxidation, scavenge oxygen free radicals, inhibit the formation of reactive oxygen radicals and prevent the depletion of endogenous antioxidants, such as vitamin E and glutathione. Moreover, carvedilol blocks the oxidation of low-density lipoproteins (LDL), and thereby prevents the formation of oxidized-LDL which is believed to stimulate foam cell formation and augment the development of atherosclerotic plaque. The ability of carvedilol to prevent the formation of oxidized LDL, in addition to the general anti-oxidant properties of the compound, results in the protection of the endothelium from oxygen free radical injury, and thereby prevents the subsequent events triggered by endothelial damage. Recently, carvedilol has also been shown to inhibit vascular smooth muscle cell proliferation and migration. Because carvedilol can inhibit vascular smooth muscle cell proliferation induced by a wide variety of mitogens (e.g. growth factors, angiotensin II, endothelin, thrombin), it is likely that the site of inhibition occurs at some point beyond the specific mitogen receptors, possibly at a distal common pathway that affects the smooth muscle cell cycle. These unique activities of carvedilol have also been confirmed in vivo in a rat model of neointimal formation following vascular injury by balloon angioplasty, where vascular smooth muscle cell migration and proliferation are the key processes involved in the formation of neointima leading to vascular stenosis. In this model, carvedilol suppressed neointimal growth to a remarkable extent ( > 85% inhibition of neointimal formation) at a dose that is similar to the antihypertensive dose used clinically in hypertensive patients. Taken together, these unique multiple actions of carvedilol provide not only for adequate control of elevated blood pressure, but may also provide for protection of the heart and vasculature from secondary damage due to hypertension itself, as well as from other causes, such as ischaemia, pressure overload, shear stress, vascular injury and atherosclerosis.

Cardiac hypertrophy and failure in hypertension.

Left ventricular hypertrophy is both a major adaptive response to chronic pressure overload and an important risk factor in patients with hypertension. It is now well appreciated that structural changes in the myocardium are mediated not only by the mechanical stress of pressure overload but also by various neurohormonal substances that exert trophic effects on myocytes and non-myocytes in the heart. Both earlier recognition and improved understanding of cardiac hypertrophy may lead to more effective therapeutic strategies for hypertension. This review focuses on the underlying mechanisms in hypertensive heart disease that lead to heart failure.

Pulmonary blood volume: the response to afterload in normal subjects and patients with previous myocardial infarction.

To analyze the effects of acute elevations in arterial blood pressure on pulmonary blood volume (PBV) and left ventricular function, eight normal controls and ten patients with previous myocardial infarctions were studied using equilibrium radionuclide angiography during the infusion of phenylephrine. Radionuclide estimates of PBV did not change significantly in the control subjects (48 +/- 20 units at rest, 53 +/- 28 units after administration of atropine, and 47 +/- 20 units at the peak elevation of pressure), though cardiac output rose and pulmonary transit time declined (P less than .05). In infarct patients, resting PBV was similar to that of normals at rest (44 +/- 12 vs. 48 +/- 20, p = not significant). However, it rose significantly at the peak elevation of arterial pressure (55 +/- 12 units, P less than .05 vs. control). Transit time was greater in the patients at rest (22 +/- 15 units vs. 14 +/- 7 units in controls, P less than .01), and, unlike transit time of normals, did not decline with pressure overhead. At any level of afterload-induced increases in end-diastolic volume or decreases in ejection fraction, PBV was greater in the patients than in normals. This suggests that, while the absolute response of cardiac volume and ejection fraction to pressure overload may be quantitatively similar in normals and infarct patients, This is not mirrored by changes in PBV and transit time. In all likelihood, elevations in cardiac filling pressures and pulmonary distending pressures occur in the infarct patients. Increases in PBV may be a noninvasive reflection of both the development of incipient congestive heart failure and reduced myocardial compliance in infarct patients. In this way, pressure overload stress may be a useful technique to prospectively categorize patient populations subject to higher incidences of congestive failure.

Functional significance of altered myosin adenosine triphosphatase activity in enlarged hearts

Enlarged hearts secondary to significant pressure overload have a depressed myosin adenosine triphosphatase (ATPase) activity. With mild stress the ATPase activity may be normal or slightly elevated. Enlargement of the heart after exercise or thyroid stress results in an increased ATPase activity. Rapid myothermal techniques, in particular measurements of tension-dependent heat, were used to evaluate: (1) the relation of in vitro measurements of actin-activated ATPase activity to the in vivo behavior of myosin, and (2) the contribution of these changes to the economy of tension development and the time course of crossbridge cycling. Experiments were carried out in animals whose hearts were enlarged secondary to pressure overload (by pulmonary arterial banding) or thyrotoxic stress. In vitro actin-activated ATPase activity levels were 70 and 175 percent of normal for the pressure-overloaded and thyrotoxic hearts, respectively, while the tension-dependent heat per unit tension for the same preparations was, respectively, 78 and 154 percent of normal. Thus there is a reasonable correlation between the in vivo and in vitro measurements of contractile protein ATPase activity, which indicates that the economy of tension development is inversely related to tensiondependent heat per unit tension or actin-activated myosin ATPase activity. Analysis of these data in terms of the kinetics of ATPase activity, crossbridge behavior and tension development leads to the conclusion that in pressure overload hypertrophy the adaptation involves a decrease in the crossbridge cycling rate, an increase in crossbridge off-time and an increase in the on-time of the crossbridge. For thyrotoxic hypertrophy the adaptation involves an increase in the cycling rate, a decrease in the off-time and a decrease in the on-time. The former is adapted for slow, economical tension development and the latter for rapid, less economical tension development.