Ivor J. Benjamin

Members of the heat shock factor (HSF) family are evolutionarily conserved regulators that share a highly homologous DNA-binding domain. In mammals, HSF1 is the main factor controlling the stress-inducible expression of Hsp genes while the functions of HSF2 and HSF4 are less clear. Based on its developmental profile of expression, it was hypothesized that HSF2 may play an essential role in brain and heart development, spermatogenesis, and erythroid differentiation. To directly assess this hypothesis and better understand the underlying mechanisms that require HSF2, we generated Hsf2 knockout mice. Here, we report that Hsf2^−/− mice are viable and fertile and exhibit normal life span and behavioral functions. We conclude that HSF2, most probably because its physiological roles are integrated into a redundant network of gene regulation and function, is dispensable for normal development, fertility, and postnatal psychomotor function.

In this study, using heat shock factor 1 (Hsf1) knockout mice as a model, we tested the hypothesis that HSF1‐dependent regulation of heat shock proteins (Hsps) is required to maintain redox state and attenuate oxidative damage in the normal heart. Here we report that, in mice, HSF1 deficiency reduces cardiac expression of Hsp25, αB‐crystallin and Hsp70, but not Hsp60 and Hsp90. Consistent with the downregulation of Hsp25, for example, a significantly lower glutathione (GSH)/glutathione disulfate (GSSG) ratio was associated with the decreased activity, but not protein content, of glucose 6‐phosphate dehydrogenase. Con sequently, superoxide was generated at a higher rate, and several mitochondrial proteins, including adenine nucleotide translocase 1 (ANT1), were more oxidized by HSF1 deficiency in vivo. Oxidative damage to ANT1 protein, a structural component of the mitochondrial permeability transition pore (MPTP), decreases its catalytic activity and increases MPTP opening, respectively. Taken together, our results indicate for the first time that constitutive expression of HSP chaperones requires HSF1 activity, and that such HSF1‐dependent requirements are directly and functionally linked to maintain redox homeostasis and antioxidative defenses at normal (37°C) temperature.

Recent decades have witnessed substantial strides in our efforts to reduce both morbidity and mortality resulting from congenital and acquired forms of heart disease.1Traditional therapies using inotropic agents (eg, digoxin) for congestive heart failure (CHF) are now surpassed in efficacy by new classes of pharmacologic agents, such as angiotensin-converting enzyme (ACE) inhibitors, which exert both central (eg, myocardial remodeling) and peripheral (eg, afterload reduction) effects. New insights about the etiologic factors and progression of CHF have emerged from the mechanisms that mediate the physiologic roles of ACE inhibitors at the cellular level. At the same time, the emphasis has shifted away from the cardiomyocyte per se to consider the physiologic role of the connective tissue elements and matrix remodeling, within the extracellular milieu, in the pathophysiology of heart failure. Matrix metalloproteinases (MMPs), a large multigene class of endopeptidases, are rapidly emerging as the next molecular targets whose biologic roles are involved in a wide spectrum of human pathologies. MMP distribution in the organism reflect the scope of the clinical burden, spanning entities such as degenerative rheumatoid arthritis, cancer metastasis, periodontitis, renal disease, and certain cardiac and vascular diseases. Evidence, which is ever accumulating, suggests that MMPs and their endogenous tissue inhibitors (TIMPs) are possible targets for future therapeutic strategies in cardiovascular diseases. Both challenges and opportunities exist to reduce restenosis after angioplasty, to increase graft potency after coronary artery bypass, and to improve the survival of inheritable disorders, such as hypertrophic cardiomyopathy and Marfan syndrome. Hence, the primary goals in this review are to demystify the extracellular matrix (ECM), to provide a bench-to-bedside overview of the basic foundations in this burgeoning field, and to lay out a conceptual framework for the clinician to consider new therapeutic strategies on the horizon targeted to interactions between MMPs and TIMPs in …