No abstract

Enhancement of MMP-2 and MMP-9 in cardiac myocytes in response to doxorubicin is mediated by the cooperation of ERK, JNK, and p38 kinase pathways, most of which are redox dependent.

Adipose tissue inflammation mediates the association between excessive body fat accumulation and several chronic inflammatory diseases. A high prevalence of obesity-associated adipose tissue inflammation was observed not only in patients with cardiovascular conditions but also in patients with inflammatory bowel diseases, abdominal aortic aneurysm, or cardiorenal syndrome. In addition to excessive caloric intake, other triggers promote visceral adipose tissue inflammation followed by chronic, low-grade systemic inflammation. The infiltration and accumulation of immune cells in the inflamed and hypertrophied adipose tissue promote the production of inflammatory cytokines, contributing to target organ damages. This comorbidity seems to delimit subgroups of individuals with systemic adipose tissue inflammation and more severe chronic inflammatory diseases that are refractory to conventional treatment. This review highlights the association between adipose tissue immune response and the pathophysiology of visceral adiposity-related chronic inflammatory diseases, while suggesting several new therapeutic strategies.

The mechanism by which different doses of doxorubicin may induce different stress-response cellular programs is not well understood. A recent study showed that the level of telomere dysfunction may induce senescence or apoptosis. We investigated the pathways to both apoptosis and senescence in neonatal rat cardiomyocytes and in H9c2 cells exposed to a single pulsed incubation with low or high doses of doxorubicin. High-dose doxorubicin strongly reduces TRF2 expression while enhancing TRF1 expression, and it determines early apoptosis. Low-dose doxorubicin induces downregulation of both TRF2 and TRF1, and it also increases the senescence-associated-␤-galactosidase activity, downregulates the checkpoint kinase Chk2, induces chromosomal abnormalities, and alters the cell cycle. The involvement of TRF1 and TRF2 with apoptosis and senescence was assessed by short interfering RNA interference. The cells maintain telomere dysfunction and a senescent phenotype over time and undergo late death. The increase in the phase Ͼ4N and the presence of micronuclei and anaphase bridges indicate that cells die by mitotic catastrophe. p38 modulates TRF2 expression, whereas JNK and cytoplasmic p53 regulate TRF1. Pretreatment with specific inhibitors of MAPKs and p53 may either attenuate the damage induced by doxorubicin or shift the cellular response to stress from senescence to apoptosis. In conclusion, various doses of doxorubicin induce differential regulation of TRF1 and TRF2 through p53 and MAPK, which is responsible for inducing either early apoptosis or senescence and late death due to mitotic catastrophe. p53; mitogen-activated protein kinases; anthracyclines THE CLINICAL USE OF ANTHRACYCLINES in anti-cancer treatment is limited by their adverse cardiotoxic effects, which include cardiomyopathy and heart failure (22). At high doses, cardiotoxicity often occurs within a few months, whereas low doses rarely cause deterioration of ventricular function in the first year after therapy (58). However, there is now increasing evidence that, several years after therapy, one of three patients treated with low-dose anthracyclines develops hypokinetic cardiomyopathy (21). A number of mechanisms have been proposed to explain anthracycline cardiotoxicity. Although the most accredited hypothesis states that anthracyclines induce myocyte loss through oxidative stress and apoptotic cell death (3, 48), there is controversy whether apoptosis contributes to late onset cardiotoxicity induced by low doses of doxorubicin (4). Maejima et al. (34) recently showed that when cultured neonatal rat cardiomyocytes are exposed to low concentrations of doxorubicin, the cells do not enter apoptotic program but exhibit a senescence-like phenotype. The hallmark of cellular senescence is the cell cycle arrest that is accompanied by important changes in many aspects of cell morphology (20,38). Senescence is the result of changes in the expression of many proteins that regulates cell cycle, cytoskeletal function, and cellular architecture and causes impairment o...

Regardless of the clinical phase of heart failure, elevated levels of activity and of circulating metalloproteinase protein levels suggest the presence of persistent extracellular remodeling in patients with heart failure.