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Cancer patients receiving anthracycline-based chemotherapy (Anth-bC) may experience early cardiac fibrosis, which could be an important contributing mechanism to the development of impaired left ventricular (LV) function. Substance P, a neuropeptide that predominantly acts via the neurokinin 1 receptor (NK-1R), contributes to adverse myocardial remodelling and fibrosis in other cardiomyopathies. We sought to determine if NK-1R blockade is effective against doxorubicin (Dox – a frequently used Anth-bC)-induced cardiac fibrosis and cardiomyocyte apoptosis. In addition, we explored the direct effects of Dox on cardiac fibroblasts. Male Sprague-Dawley rats were randomised to receive saline, six cycles of Dox (1.5 mg Dox/kg/cycle) or Dox with an NK-1R antagonist (L732138, 5 mg/kg/daily through Dox treatment). At 8 weeks after the initial dose of Dox, LV function and histopathological myocardial fibrosis and cell apoptosis were assessed. Collagen secretion was measured in vitro to test direct Dox activation of cardiac fibroblasts. Rats undergoing Dox treatment (9 mg/kg cumulative dose) developed cardiac fibrosis and cardiomyocyte apoptosis. NK-1R blockade partially mitigated cardiac fibrosis while completely preventing cardiomyocyte apoptosis. This resulted in improved diastolic function. Furthermore, we found that Dox had direct effects on cardiac fibroblasts to cause increased collagen production and enhanced cell survival. This study demonstrates that cardiac fibrosis induced by Anth-bC can be reduced by NK-1R blockade. The residual fibrotic response is likely due to direct Dox effects on cardiac fibroblasts to produce collagen. [ABSTRACT FROM AUTHOR]

Background Fibulin-1 and soluble urokinase-type plasminogen activator receptor (suPAR) emerged as mediators in the development of sclerotic disease. SuPAR along with C-reactive protein (CRP) and albumin delineate inflammatory processes associated with extracellular matrix turnover in atherosclerosis. We explored the independent relationship of fibulin-1 with these inflammatory markers in a bi-ethnic South African population. Methods This study included 290 Africans (men: n = 130 and women: n = 160) and 343 sex- and age-matched Caucasians (men: n = 160 and women: n = 183). Serum fibulin-1, suPAR, CRP and albumin levels were measured along with conventional cardiovascular and metabolic variables. Results In both single and age-adjusted regression analyses, fibulin-1 correlated with both suPAR and albumin in African men and with suPAR in Caucasian men. These findings were absent in women. In multivariate regression analysis, these associations were confirmed in African men (R 2 = 0.22; β=0.329; p < 0.001) and Caucasian men (R 2 = 0.14; β=0.234; p = 0.008). Fibulin-1 independently associated positively with suPAR in all men, but inversely with albumin in African men only. Conclusions These results are indicating the presence of potential subclinical inflammation (suPAR) within the extracellular matrix of endothelial tissue, contributing to the potential onset of cardiac fibrosis or vascular sclerosis among these South African men with lower albumin levels. [ABSTRACT FROM AUTHOR]

Background: Cancer patients receiving anthracycline-based chemotherapy (Anth-bC) may experience early cardiac fibrosis, which could be an important contributing mechanism to the development of impaired left ventricular (LV) function. Substance P, a neuropeptide that predominantly acts via the neurokinin 1 receptor (NK-1R), contributes to adverse myocardial remodelling and fibrosis in other cardiomyopathies. We sought to determine if NK-1R blockade is effective against doxorubicin (Dox - a frequently used Anth-bC)-induced cardiac fibrosis and cardiomyocyte apoptosis. In addition, we explored the direct effects of Dox on cardiac fibroblasts.Methods: Male Sprague-Dawley rats were randomised to receive saline, six cycles of Dox (1.5mg Dox/kg/cycle) or Dox with an NK-1R antagonist (L732138, 5mg/kg/daily through Dox treatment). At 8 weeks after the initial dose of Dox, LV function and histopathological myocardial fibrosis and cell apoptosis were assessed. Collagen secretion was measured in vitro to test direct Dox activation of cardiac fibroblasts.Results: Rats undergoing Dox treatment (9mg/kg cumulative dose) developed cardiac fibrosis and cardiomyocyte apoptosis. NK-1R blockade partially mitigated cardiac fibrosis while completely preventing cardiomyocyte apoptosis. This resulted in improved diastolic function. Furthermore, we found that Dox had direct effects on cardiac fibroblasts to cause increased collagen production and enhanced cell survival.Conclusions: This study demonstrates that cardiac fibrosis induced by Anth-bC can be reduced by NK-1R blockade. The residual fibrotic response is likely due to direct Dox effects on cardiac fibroblasts to produce collagen. [ABSTRACT FROM AUTHOR]