Occlusion of the diseased coronary artery in humans causes acute myocardial infarction, survivors of which have a high risk for the development of chronic heart failure. Cardiac myocytes and vascular endothelial cells produce endothelin-1 (refs 2-4), which increases the contractility of cardiac muscle and of vascular smooth muscle cells. Endothelin-1 also exerts long-term effects such as myocardial hypertrophy, and causes cellular injury in cardiac myocytes. Production of endothelin-1 is markedly increased in the myocardium of rats with heart failure, and acute application of an endothelin-receptor antagonist decreases myocardial contractility in such rats, indicating that myocardial endothelin-1 may help to support contractility of the failing heart. But we report here that the upregulated myocardial endothelin system may contribute to the progression of chronic heart failure, because long-term treatment with an endothelin-receptor antagonist greatly improved the survival of rats with chronic heart failure. This beneficial effect was accompanied by significant amelioration of left ventricular dysfunction and prevention of ventricular remodelling, in which there is usually an increase in the ventricular mass and cavity enlargement of the ventricle.

Endothelin-1 (ET-1) is known to have potent contractile and proliferative effects on vascular smooth muscle cells and is known to induce myocardial cell hypertrophy. We studied the pathophysiological role of endogenous ET-1 in rats with monocrotaline-induced pulmonary hypertension. Four-week-old rats were given a single subcutaneous injection of 60 mg/kg monocrotaline (MCT rats) or saline (control rats) and were killed after 6, 10, 14, 18, and 25 days. In the MCT rats, right ventricular systolic pressure progressively increased and right ventricular hypertrophy developed in a parallel fashion. The venous plasma ET-1 concentration also progressively increased, and this increase preceded the development of pulmonary hypertension. The isolated pulmonary artery exhibited a significantly weaker response to ET-1 in the MCT rats on day 25 but not on days 6 and 14. In the MCT rats, the expression of prepro ET-1 mRNA as measured by Northern blot analysis significantly increased in the heart on days 18 and 25, whereas it gradually decreased in the lungs. The peptide level of ET-1 in the lungs also significantly decreased in the pulmonary hypertensive stage. The expression of prepro ET-1 mRNA had increased by day 6 only in the kidneys. disease, valvular heart disease, and left ventricular failure) and pulmonary diseases (eg, emphysema, lung fibrosis, and obstructive airway disease) are often accompanied by pulmonary hypertension, and the severity of pulmonary hypertension is one determinant of the prognosis of such patients.' Although some researchers believe that pulmonary vasoconstriction plays a role in the pathogenesis of pulmonary hypertension,"2 the mechanism for the progression of pulmonary hypertension is still poorly understood. Received October 26, 1992; accepted July 13, 1993. Endothelin-1 (ET-1), a potent endothelium-derived vasoconstrictor peptide, was recently identified.3 This peptide induces proliferation of vascular smooth muscle cells.4 ET-1 has several properties suggestive of a potential pathophysiological role in pulmonary hypertension. First, ET-1 contracts isolated pulmonary vessels5 and increases pulmonary vascular resistance.6'7 Second, ET-1 has a mitogenic effect on vascular smooth muscle cells4'8'9 and fibroblasts,'0"' consistent with a role in vascular remodeling, a prominent finding in pulmonary hypertensive stages. ET-1 has also been reported to be produced by nonvascular tissues such as the heart, kidneys, and central nervous system.'2"3 It has been demonstrated that prepro ET-1 mRNA is expressed in cultured rat cardiomyocytes'4 and that ET-1-like immunoreactivity exists in the renal cortex and medulla of rats.15 In the heart, ET-1 induces myocardial cell hypertrophy'6 and has positive inotropic'7 and chronotropic'8 effects.A single subcutaneous injection of monocrotaline (MCT), a pyrrolizidine alkaloid, causes pulmonary hyby guest on

In the present study, we demonstrated that the production of ET-1 in the heart is markedly increased and that the density of myocardial ET receptors is significantly elevated in the CHF rats. Intravenous BQ-123 infusion significantly reduced both heart rate and LV+dP/dt(max) in the CHF rats but not in the sham-operated rats. Therefore, the ET receptor-mediated signal transduction system in the heart appears to be markedly stimulated in the CHF rats, and endogenous ET-1 may be involved in the maintenance of the cardiac function in these rats.

Hypertrophy allows the heart to adapt to workload but culminates in later pump failure; how it is achieved remains uncertain. Previously, we showed that hypertrophy is accompanied by activation of cyclin T/Cdk9, which phosphorylates the C-terminal domain of the large subunit of RNA polymerase II, stimulating transcription elongation and pre-mRNA processing; Cdk9 activity was required for hypertrophy in culture, whereas heart-specific activation of Cdk9 by cyclin T1 provoked hypertrophy in mice. Here, we report that aMHC-cyclin T1 mice appear normal at baseline yet suffer fulminant apoptotic cardiomyopathy when challenged by mechanical stress or signaling by the G-protein Gq. At pathophysiological levels, Cdk9 activity suppresses many genes for mitochondrial proteins including master regulators of mitochondrial function (peroxisome proliferator-activated receptor gamma coactivator 1 (PGC-1), nuclear respiratory factor-1). In culture, cyclin T1/Cdk9 suppresses PGC-1, decreases mitochondrial membrane potential, and sensitizes cardiomyocytes to apoptosis, effects rescued by exogenous PGC-1. Cyclin T1/Cdk9 inhibits PGC-1 promoter activity and preinitiation complex assembly. Thus, chronic activation of Cdk9 causes not only cardiomyocyte enlargement but also defective mitochondrial function, via diminished PGC-1 transcription, and a resulting susceptibility to apoptotic cardiomyopathy.

An ageostrophic version of Phillips’ model is studied. All instabilities found are systematically interpreted in terms of resonance of wave components. The instability occurs if there is a pair of wave components which propagate in the opposite direction to the basic flow and these wave components have almost the same Doppler-shifted frequency. A new instability, identified as a resonance between the Kelvin wave and the Rossby waves, is found at Froude number F ≈ 0.7. The Rossby waves are almost completely in geostrophic balance while the ageostrophic Kelvin wave is the same as in a one-layer system. Doppler shifting matches frequencies which would otherwise be very different. This instability is presumably the mechanism of the frontal instability observed by Griffiths & Linden (1982) in a laboratory experiment. Ageostrophic, baroclinic instability with non-zero phase speed is also observed in the numerical calculation. This instability is caused by resonance between different geostrophic modes.

Pressure overload, such as hypertension, to the heart causes pathological cardiac hypertrophy, whereas chronic exercise causes physiological cardiac hypertrophy, which is defined as athletic heart. There are differences in cardiac properties between these two types of hypertrophy. We investigated whether mRNA expression of various cardiovascular regulating factors differs in rat hearts that are physiologically and pathologically hypertrophied, because we hypothesized that these two types of cardiac hypertrophy induce different molecular phenotypes. We used the spontaneously hypertensive rat (SHR group; 19 wk old) as a model of pathological hypertrophy and swim-trained rats (trained group; 19 wk old, swim training for 15 wk) as a model of physiological hypertrophy. We also used sedentary Wistar-Kyoto rats as the control group (19 wk old). Left ventricular mass index for body weight was significantly higher in SHR and trained groups than in the control group. Expression of brain natriuretic peptide, angiotensin-converting enzyme, and endothelin-1 mRNA in the heart was significantly higher in the SHR group than in control and trained groups. Expression of adrenomedullin mRNA in the heart was significantly lower in the trained group than in control and SHR groups. Expression of beta(1)-adrenergic receptor mRNA in the heart was significantly higher in SHR and trained groups than in the control group. Expression of beta(1)-adrenergic receptor kinase mRNA, which inhibits beta(1)-adrenergic receptor activity, in the heart was markedly higher in the SHR group than in control and trained groups. We demonstrated for the first time that the manner of mRNA expression of various cardiovascular regulating factors in the heart differs between physiological and pathological cardiac hypertrophy.

Peroxisome proliferator-activated receptor (PPAR)-␣, a transcriptional activator, regulates genes of fatty acid (FA) metabolic enzymes. To study the contribution of PPAR-␣ to exercise training-induced improvement of FA metabolic capacity in the aged heart, we investigated whether PPAR-␣ signaling and expression of its target genes in the aged heart are affected by exercise training. We used hearts of sedentary young rat (4 mo old), sedentary aged rat (23 mo old), and swim-trained aged rat (23 mo old, training for 8 wk). The mRNA and protein expression of PPAR-␣ in the heart was significantly lower in the sedentary aged rats compared with the sedentary young rats and was significantly higher in the swim-trained aged rats compared with the sedentary aged rats. The activity of PPAR-␣ DNA binding to the transcriptional regulating region on the FA metabolic enzyme genes, the mRNA expression of 3-hydroxyacyl CoA dehydrogenase (HAD) and carnitine palmitoyl transferase-I, which are PPAR-␣ target genes, and the enzyme activity of HAD in the heart altered in association with changes of the myocardial PPAR-␣ mRNA and protein levels. These findings suggest that exercise training improves aging-induced downregulation in myocardial PPAR-␣-mediated molecular system, thereby contributing to the improvement of the FA metabolic enzyme activity in the trained-aged hearts.peroxisome proliferator-activated receptor-␣; swimming training; aged rat; fatty acid THE HEART is known for its ability to produce energy from fatty acids (FA) because of its important ␤-oxidation equipment, but it can also derive energy from several other substrates, including glucose and lactate (10, 23). On a physiological condition, FA is considered to account for 60-70% of oxygen consumption for energy production in the heart (23). However, FA metabolic capacity in the heart is reduced by aging (19, 32).It has been reported that exercise training improved an aging-induced decrease of FA metabolic capacity in the heart (7, 18, 25, 32). However, the mechanisms for improving FA metabolic capacity in the heart by exercise training are unclear.Peroxisome proliferator-activated receptor (PPAR)-␣ is a member of the nuclear receptor transcription factor superfamily and is mainly expressed in the heart, liver, and kidney (2,13,29). The recent studies indicated that PPAR-␣ plays a critical role in the expression of genes involved in FA metabolism (13). PPAR-␣ heterodimerizes with the retinoid X receptor (RXR-␣) to bind to peroxisome proliferator-response elements (PPRE) in the upstream regions of a number of genes involved in metabolic homeostasis (13,29). PPAR-␣ regulates target genes encoding FA metabolic (␤-oxidation) enzymes and FA transporters such as FA binding protein, carnitine palmitoyl transferase-I (CPT-I), acyl-CoA synthase, 3-hydroxyacyl CoA dehydrogenase (HAD), apolipoproteins, and so on, suggesting that PPAR-␣ plays an important role in FA metabolic homeostasis (2,5,17,29). However, it is unknown whether the aging and subsequent exercise training affect...

Background-Peroxisome proliferator-activated receptor-␣ (PPAR-␣) is a lipid-activated nuclear receptor that negatively regulates the vascular inflammatory gene response by interacting with transcription factors, nuclear factor-B, and AP-1. However, the roles of PPAR-␣ activators in endothelin (ET)-1-induced cardiac hypertrophy are not yet known. Methods and Results-First, in cultured neonatal rat cardiomyocytes, a PPAR-␣ activator, fenofibrate (10 mol/L), and PPAR-␣ overexpression markedly inhibited the ET-1-induced increase in protein synthesis. Second, fenofibrate markedly inhibited ET-1-induced increase in c-Jun gene expression and phosphorylation of c-Jun and JNK. These results suggest that this PPAR-␣ activator interferes with the formation and activation of AP-1 protein induced by ET-1 in cardiomyocytes. Third, fenofibrate significantly inhibited the increase of ET-1 mRNA level by ET-1, which was also confirmed by luciferase assay. Electrophoretic mobility shift assay revealed that fenofibrate significantly decreased the ET-1-stimulated or phorbol 12-myristate 13-acetate-stimulated AP-1 DNA binding activity, and the nuclear extract probe complex was supershifted by anti-c-Jun antibody. Fourth, 24 hours after aortic banding (AB) operation, fenofibrate treatment significantly inhibited left ventricular hypertrophy and hypertrophy-related gene expression pattern (ET-1, brain natriuretic peptide, and ␤-myosin heavy chain mRNA) in AB rats. Conclusions-These results suggest that PPAR-␣ activation interferes with the signaling pathway of ET-1-induced cardiac hypertrophy through negative regulation of AP-1 binding activity, partly via inhibition of the JNK pathway in cultured cardiomyocytes. We also revealed that fenofibrate treatment inhibited left ventricle hypertrophy and phenotypic changes in cardiac gene expression in AB rats in vivo.