In a cohort of outpatients with established HF, higher BMIs were associated with lower mortality risks; overweight and obese patients had lower risk of death compared with those at a healthy weight. Understanding the mechanisms and impact of the "obesity paradox" in patients with HF is necessary before recommendations are made concerning weight and weight control in this population.

Hypoxia-inducible transcription factor 1 (HIF-1) and HIF-2␣ regulate the expression of an expansive array of genes associated with cellular responses to hypoxia. Although HIF-regulated genes mediate crucial beneficial short-term biological adaptations, we hypothesized that chronic activation of the HIF pathway in cardiac muscle, as occurs in advanced ischemic heart disease, is detrimental. We generated mice with cardiac myocyte-specific deletion of the von Hippel-Lindau protein (VHL), an essential component of an E3 ubiquitin ligase responsible for suppressing HIF levels during normoxia. These mice were born at expected frequency and thrived until after 3 months postbirth, when they developed severe progressive heart failure and premature death. VHL-null hearts developed lipid accumulation, myofibril rarefaction, altered nuclear morphology, myocyte loss, and fibrosis, features seen for various forms of human heart failure. Further, nearly 50% of VHL ؊/؊ hearts developed malignant cardiac tumors with features of rhabdomyosarcoma and the capacity to metastasize. As compelling evidence for the mechanistic contribution of HIF-1␣, the concomitant deletion of VHL and HIF-1␣ in the heart prevented this phenotype and restored normal longevity. These findings strongly suggest that chronic activation of the HIF pathway in ischemic hearts is maladaptive and contributes to cardiac degeneration and progression to heart failure.In the cardiovascular system, hypoxia is encountered in a number of important clinical settings, including sleep apnea, chronic obstructive pulmonary disease, and, most commonly, ischemic heart disease (IHD). Myocardial hypoxia, as a component of ischemia, may also occur in other common clinical conditions, such as valve disease, pathological cardiac hypertrophy, and severe systemic hypertension. As such, understanding how hypoxia-induced molecular changes affect the heart is of great importance. Altered gene expression mediated by hypoxia-inducible transcription factor 1␣ (HIF-1␣) and HIF-2␣ is one of the most fundamental and ubiquitous mechanisms whereby biological adaptations to hypoxia occur. The HIFs are basic helix-loop-helix transcription factors that regulate the expression of a wide repertoire of genes involved in a myriad of biological functions, including angiogenesis, apoptosis, and cellular metabolism (14,17,51). A third family member, HIF-3␣, lacks a transcriptional activation domain and may act as a competitive inhibitor of HIF-1␣ and -2␣ activity (41).Although HIF-1␣ and -2␣ appear to bind the same hypoxia response elements (HREs) in hypoxia-inducible genes, it has been established that they preferentially regulate different genes in different cell types and therefore are not redundant.The role of HIF-1␣ in the transcriptional control of angiogenesis has led to the ongoing development of HIF-1␣ as a therapeutic stimulator of angiogenesis in IHD and peripheral vascular disease (12,15,48,60), although clinical development of HIF-2␣ for this purpose has also been considered. Others and we ...

Although intimately positioned between metabolic substrates in the bloodstream and the tissue parenchymal cells that require these substrates, a major role of the vascular endothelium in the regulation of tissue metabolism has not been widely appreciated. We hypothesized that via control of transendothelial glucose transport and contributing paracrine mechanisms the endothelium plays a major role in regulating organ and tissue glucose metabolism. We further hypothesized that the hypoxia-inducible factor -1α (HIF-1α) plays an important role in coordinating these endothelial functions. To test these hypotheses, we generated mice with endothelial cell-specific deletion of HIF-1α. Loss of HIF in the endothelium resulted in significantly increased fasting blood glucose levels, a blunted insulin response with delayed glucose clearance from the blood after i.v. loading, and significantly decreased glucose uptake into the brain and heart. Endothelial HIF-1α knockout mice also exhibited a reduced cerebrospinal fluid/blood glucose ratio, a finding consistent with reduced transendothelial glucose transport and a diagnostic criterion for the Glut1 deficiency genetic syndrome. Endothelial cells from these mice demonstrated decreased Glut1 levels and reduced glucose uptake that was reversed by forced expression of Glut1. These data strongly support an important role of the vascular endothelium in determining whole-organ glucose metabolism and indicate that HIF-1α is a critical mediator of this function.transcription | transporter | microvascular

The largest subgroup of integrins is that containing the ␤1 subunit. ␤1 integrins have been implicated in a wide array of biological processes ranging from adhesion to cell growth, organogenesis, and mechanotransduction. Global deletion of ␤1 integrin expression results in embryonic death at ca. embryonic day 5 (E5), a developmental time point too early to determine the effects of this integrin on vascular development. To elucidate the specific role of ␤1 integrin in the vasculature, we conditionally deleted the ␤1 gene in the endothelium. Homozygous deletion of ␤1 integrins in the endothelium resulted in failure of normal vascular patterning, severe fetal growth retardation, and embryonic death at E9.5 to 10, although there were no overt effects on vasculogenesis. Heterozygous endothelial ␤1 gene deletion did not diminish fetal or postnatal survival, but it reduced ␤1 subunit expression in endothelial cells from adult mice by approximately 40%. These mice demonstrated abnormal vascular remodeling in response to experimentally altered in vivo blood flow and diminished vascularization in healing wounds. These data demonstrate that endothelial expression of ␤1 integrin is required for developmental vascular patterning and that endothelial ␤1 gene dosing has significant functional effects on vascular remodeling in the adult. Understanding how ␤1 integrin expression is modulated may have significant clinical importance.The largest subgroup of integrins is that containing the ␤1 subunit (5, 6). ␤1 integrins have been implicated in a wide array of biological processes, including cell migration, adhesion, formation of basement membrane, and control of the cell cycle (5,6,11,13,20,25,31). They have also been purported to play an essential role in angiogenesis, although the data supporting this role have been obtained in an indirect manner using techniques such as blocking antibodies or RNA interference (15,22,30). The role of ␤1 integrin in angiogenesis has also been inferred by the finding that tumor formation by ␤1 null cells is defective, with absence of tumor vascularization (4). Further, ␤1 integrin expression is highly upregulated in the central nervous system vasculature during maturation, and it has thus been proposed that this integrin plays an important role in maintaining the integrity of the mature central nervous system vasculature (26). Interestingly, cerebral cavernous malformations (CCMs) have been linked to defects in the KRIT-1 gene, the protein product of which interacts with the integrin cytoplasmic domain-associated protein 1 alpha (ICAP-1␣) (24,(36)(37)(38). ICAP-1␣ directly binds the cytoplasmic tail of ␤1 integrin. Further, the ICAP-1␣ binding sites for both KRIT-1 and ␤1 integrin are similar, and both contain a crucial NPXY motif (36). It has thus been postulated that KRIT-1 and ␤1 integrin compete for binding to ICAP-1␣ and that this competition modulates ␤1 integrin signaling and function. Therefore, the vascular defects observed in patients with KRIT-1 gene mutations may involve abnormal ␤1 i...

Effective primary and secondary prevention and advances in cardiac surgery have significantly improved the care and outcomes of patients with myocardial ischemia. While timely reperfusion has proved to be an invaluable tool, ischemia-reperfusion injury represents a mechanism that may limit its effectiveness. Numerous experimental studies have shown effective protection from ischemia-reperfusion injury in animal models, but translation into clinical practice has been less successful. This article summarizes the role of ischemia-reperfusion injury in the pathophysiology of ischemic heart disease and gives an overview of the various modalities that have been developed in order to provide myocardial protection from reperfusion injury in clinical practice.