Circulation research
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Circulation research · Jan 2010
ReviewThe vulnerability of the heart as a pluricellular paracrine organ: lessons from unexpected triggers of heart failure in targeted ErbB2 anticancer therapy.
In this review, we address clinical aspects and mechanisms of ventricular dysfunction induced by anticancer drugs targeted to the ErbB2 receptor. ErbB2 antagonists prolong survival in cancer, but also interfere with homeostatic processes in the heart. ErbB2 is a coreceptor for ErbB4, which is activated by neuregulin-1. ⋯ Differences in the mode of action of individual ErbB2 antagonists affect their impact on the function of the ventricle, considered to be "on-target" or "off-target." Establishing the relation between the cardiac side effects of ErbB2 antagonists and their impact on paracrine ventricular control mechanisms may direct the design of a next generation of ErbB2 inhibitors. For cardiologists, there are lessons to be learned from the unexpected side effects of ErbB2-targeted cancer therapy. The vulnerability of the heart as a pluricellular paracrine system appears greater than anticipated and intercellular crosstalk an essential component of its functional and structural integrity.
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Circulation research · Dec 2009
Comparative StudyAngiotensin II-induced oxidative stress resets the Ca2+ dependence of Ca2+-calmodulin protein kinase II and promotes a death pathway conserved across different species.
Angiotensin (Ang) II-induced apoptosis was reported to be mediated by different signaling molecules. Whether these molecules are either interconnected in a single pathway or constitute different and alternative cascades by which Ang II exerts its apoptotic action, is not known. ⋯ (1) The Ang II-induced apoptotic cascade converges in both species, in a common pathway mediated by ROS-dependent CaMKII activation which results in p38MAPK activation and apoptosis. (2) In the presence of Ang II or ROS, CaMKII may be activated at subdiastolic Ca(2+) concentrations, suggesting a new mechanism by which ROS reset the Ca(2+) dependence of CaMKII to extremely low Ca(2+) levels.
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Circulation research · Aug 2009
Heart-infiltrating prominin-1+/CD133+ progenitor cells represent the cellular source of transforming growth factor beta-mediated cardiac fibrosis in experimental autoimmune myocarditis.
Myocardial fibrosis is a hallmark of inflammation-triggered end-stage heart disease, a common cause of heart failure in young patients. ⋯ Taken together, heart-infiltrating prominin-1(+) progenitors are the major source of subsequent TGF-beta-triggered cardiac fibrosis in experimental autoimmune myocarditis. Recognizing the critical, cytokine-dependent role of bone marrow-derived progenitors in cardiac remodeling might result in novel treatment concepts against inflammatory heart failure.