Histone deacetylase signaling in cardioprotection.

Cardiovascular disease (CVD) represents a major challenge for health care systems, both in terms of the high mortality associated with it and the huge economic burden of its treatment. Although CVD represents a diverse range of disorders, they share common compensatory changes in the heart at the structural, cellular, and molecular level that, in the long term, can become maladaptive and lead to heart failure. Treatment of adverse cardiac remodeling is therefore an important step in preventing this fatal progression. Although previous efforts have been primarily focused on inhibition of deleterious signaling cascades, the stimulation of endogenous cardioprotective mechanisms offers a potent therapeutic tool. In this review, we discuss class I and class II histone deacetylases, a subset of chromatin-modifying enzymes known to have critical roles in the regulation of cardiac remodeling. In particular, we discuss their molecular modes of action and go on to consider how their inhibition or the stimulation of their intrinsic cardioprotective properties may provide a potential therapeutic route for the clinical treatment of CVD.

Autonomous folding of interdomain regions of a modular polyketide synthase.

Domains within the multienzyme polyketide synthases are linked by noncatalytic sequences of variable length and unknown function. Recently, the crystal structure was reported of a portion of the linker between the acyltransferase (AT) and ketoreductase (KR) domains from module 1 of the erythromycin synthase (6-deoxyerythronolide B synthase), as a pseudodimer with the adjacent ketoreductase (KR). On the basis of this structure, the homologous linker region between the dehydratase (DH) and enoyl reductase (ER) domains in fully reducing modules has been proposed to occupy a position on the periphery of the polyketide synthases complex, as in porcine fatty acid synthase. We report here the expression and characterization of the same region of the 6-deoxyerythronolide B synthase module 1 AT-KR linker, without the adjacent KR domain (termed DeltaN AT1-KR1), as well as the corresponding section of the DH-ER linker. The linkers fold autonomously and are well structured. However, analytical gel filtration and ultracentrifugation analysis independently show that DeltaN AT1-KR1 is homodimeric in solution; site-directed mutagenesis further demonstrates that linker self-association is compatible with the formation of a linker-KR pseudodimer. Our data also strongly indicate that the DH-ER linker associates with the upstream DH domain. Both of these findings are incompatible with the proposed model for polyketide synthase architecture, suggesting that it is premature to allocate the linker regions to a position in the multienzymes based on the solved structure of animal fatty acid synthase.

The role of endothelin-1 in the sympathetic nervous system in the heart.

Endothelin-1 (ET1) is a peptide that was initially identified as a strong inductor of vascular contraction. In the last 25 years, there have been several biological processes identified in which ET1 seems to play a critical role. In particular, genetic studies have unveiled that ET1 is important for neuronal development, growth and function. Experimental studies identified ET1 as a regulator of the interaction between sympathetic neurons and cardiac myocytes. This might be of clinical importance since patients suffering from heart failure are characterized by disrupted norepinephrine homeostasis in the heart. This review summarizes the important findings on the role of ET1 for sympathetic neurons and norepinephrine homeostasis in the heart.