The interleukin-6 cytokines, acting via gp130 receptor pathways, play a pivotal role in the reduction of cardiac injury induced by mechanical stress or ischemia and in promoting subsequent adaptive remodeling of the heart. We have now identified the small proline-rich repeat proteins (SPRR) 1A and 2A as downstream targets of gp130 signaling that are strongly induced in cardiomyocytes responding to biomechanical/ischemic stress. Upregulation of SPRR1A and 2A was markedly reduced in the gp130 cardiomyocyte-restricted knockout mice. In cardiomyocytes, MEK1/2 inhibitors prevented SPRR1A upregulation by gp130 cytokines. Furthermore, binding of NF-IL6 (C/EBPb) and c-Jun to the SPRR1A promoter was observed after CT-1 stimulation. Histological analysis revealed that SPRR1A induction after mechanical stress of pressure overload was restricted to myocytes surrounding piecemeal necrotic lesions. A similar expression pattern was found in postinfarcted rat hearts. Both in vitro and in vivo ectopic overexpression of SPRR1A protected cardiomyocytes against ischemic injury. Thus, this study identifies SPRR1A as a novel stress-inducible downstream mediator of gp130 cytokines in cardiomyocytes and documents its cardioprotective effect against ischemic stress.

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Cardiac ET-1 mRNA levels are increased in ischemic heart failure and correlate significantly with left ventricular end-diastolic pressure 1 week after myocardial infarction. The increase in cardiac ET-1 mRNA is not accompanied by a decrease in ET receptor mRNA.

High frame rate Doppler echocardiography provides accurate non-invasive measurements of cardiac structure and function in the rat.

Changes in atrial natriuretic peptide (ANP), N-terminal proatrial natriuretic peptide and brain natriuretic peptide (BNP) were evaluated in relation to continuously monitored atrial pressures in a pacing model of heart failure. Pigs were subjected to rapid atrial pacing (225 beats min-1) for 3 weeks with adjustments of pacing frequencies if the pigs showed overt signs of cardiac decompensation. Atrial pressures were monitored by a telemetry system with the animals unsedated and freely moving. Left atrial pressure responded stronger and more rapidly to the initiation of pacing and to alterations in the rate of pacing than right atrial pressure. Plasma natriuretic peptide levels were measured by radioimmunoassay and all increased during pacing with BNP exhibiting the largest relative increase (2.9-fold increase relative to sham pigs). Multiple regression analysis with dummy variables was used to evaluate the relative changes in natriuretic peptides and atrial pressures and the strongest correlation was found between BNP and left atrial pressure with R 2=0.81. Termination of pacing resulted in rapid normalization of ANP values in spite of persistent elevations in atrial pressures. This may reflect an increased metabolism or an attenuated secretory response of ANP to atrial stretch with established heart failure. In conclusion, 3 weeks of rapid pacing induced significant increases in atrial pressures and natriuretic peptide levels. All the natriuretic peptides correlated with atrial pressures with BNP appearing as a more sensitive marker of cardiac filling pressures than ANP and N-terminal proatrial natriuretic peptide.