Hypoxia inducible factors and the response to hypoxic stress

Hypoxia-inducible factors (HIFs) are transcriptional activators that function as master regulators of oxygen homeostasis, which is disrupted in disorders affecting the circulatory system and in cancer. The role of HIFs in these diseases has been elucidated by clinical studies and by analyses of mouse models. HIFs play a protective role in the pathophysiology of myocardial ischemia due to coronary artery disease, limb ischemia due to peripheral arterial disease, pressure-overload heart failure, wound healing, and chronic rejection of organ transplants. In contrast, HIFs contribute to the pathogenesis of pulmonary arterial hypertension, systemic hypertension associated with sleep apnea, ocular neovascularization, hereditary erythrocytosis, and cancer.

Oxygen sensing, hypoxia-inducible factors, and disease pathophysiology

Cardiomyocytes exit the cell cycle and become terminally differentiated soon after birth. Therefore, in the adult heart, instead of an increase in cardiomyocyte number, individual cardiomyocytes increase in size, and the heart develops hypertrophy to reduce ventricular wall stress and maintain function and efficiency in response to an increased workload. There are two types of hypertrophy: physiological and pathological. Hypertrophy initially develops as an adaptive response to physiological and pathological stimuli, but pathological hypertrophy generally progresses to heart failure. Each form of hypertrophy is regulated by distinct cellular signalling pathways. In the past decade, a growing number of studies have suggested that previously unrecognized mechanisms, including cellular metabolism, proliferation, non-coding RNAs, immune responses, translational regulation, and epigenetic modifications, positively or negatively regulate cardiac hypertrophy. In this Review, we summarize the underlying molecular mechanisms of physiological and pathological hypertrophy, with a particular emphasis on the role of metabolic remodelling in both forms of cardiac hypertrophy, and we discuss how the current knowledge on cardiac hypertrophy can be applied to develop novel therapeutic strategies to prevent or reverse pathological hypertrophy.

Mechanisms of physiological and pathological cardiac hypertrophy

Cancer therapy has progressed remarkably in recent years. In no area has this been more apparent than in the development of "targeted therapies", particularly those using drugs that inhibit the activity of certain tyrosine kinases, activating mutations or amplifications of which are causal, or strongly contributory, to tumorigenesis. However, some of these therapies have been associated with toxicity to the heart. Here we summarize what is known about the cardiotoxicity of cancer drugs that target tyrosine kinases. We focus on basic mechanisms through which interruption of specific signalling pathways leads to cardiomyocyte dysfunction and/or death, and contrast this with therapeutic responses in cancer cells.

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Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition.

http://www.plicnihypertenze.cz/proodborniky/novinky/pah-novinky-bxd.pdf

The Right Ventricle Under Pressure: Cellular and Molecular Mechanisms of Right-Heart Failure in Pulmonary Hypertension

Cardiac hypertrophy occurs as an adaptive response to increased workload to maintain cardiac function However, prolonged cardiac hypertrophy causes heart failure, and its mechanisms are largely unknown Here we show that cardiac angiogenesis is crucially involved in the adaptive mechanism of cardiac hypertrophy and that p53 accumulation is essential for the transition from cardiac hypertrophy to heart failure Pressure overload initially promoted vascular growth in the heart by hypoxia-inducible factor-1 (Hif-1)-dependent induction of angiogenic factors, and inhibition of angiogenesis prevented the development of cardiac hypertrophy and induced systolic dysfunction Sustained pressure overload induced an accumulation of p53 that inhibited Hif-1 activity and thereby impaired cardiac angiogenesis and systolic function Conversely, promoting cardiac angiogenesis by introducing angiogenic factors or by inhibiting p53 accumulation developed hypertrophy further and restored cardiac dysfunction under chronic pressure overload These results indicate that the anti-angiogenic property of p53 may have a crucial function in the transition from cardiac hypertrophy to heart failure

Jeffrey D. Molkentin

Papers

p53-induced inhibition of Hif-1 causes cardiac dysfunction during pressure overload