Circulation research
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Circulation research · Apr 2012
ReviewContribution of impaired mitochondrial autophagy to cardiac aging: mechanisms and therapeutic opportunities.
The prevalence of cardiovascular disease increases with advancing age. Although long-term exposure to cardiovascular risk factors plays a major role in the etiopathogenesis of cardiovascular disease, intrinsic cardiac aging enhances the susceptibility to developing heart pathologies in late life. The progressive decline of cardiomyocyte mitochondrial function is considered a major mechanism underlying heart senescence. ⋯ The efficiency of this process declines with advancing age, which may play a critical role in heart senescence and age-related cardiovascular disease. The present review illustrates the putative mechanisms whereby alterations in the autophagic removal of damaged mitochondria intervene in the process of cardiac aging and in the pathogenesis of specific heart diseases that are especially prevalent in late life (eg, left ventricular hypertrophy, ischemic heart disease, heart failure, and diabetic cardiomyopathy). Interventions proposed to counteract cardiac aging through improvements in macroautophagy (eg, calorie restriction and calorie restriction mimetics) are also presented.
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Circulation research · Oct 2010
ReviewEndoplasmic reticulum stress as a therapeutic target in cardiovascular disease.
Cardiovascular disease constitutes a major and increasing health burden in developed countries. Although treatments have progressed, the development of novel treatments for patients with cardiovascular diseases remains a major research goal. The endoplasmic reticulum (ER) is the cellular organelle in which protein folding, calcium homeostasis, and lipid biosynthesis occur. ⋯ Thus, therapeutic interventions that target molecules of the UPR component and reduce ER stress will be promising strategies to treat cardiovascular diseases. In this review, we summarize the recent progress in understanding UPR signaling in cardiovascular disease and its related therapeutic potential. Future studies may clarify the most promising molecules to be investigated as targets for cardiovascular diseases.
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Circulation research · Jan 2010
ReviewThe vulnerability of the heart as a pluricellular paracrine organ: lessons from unexpected triggers of heart failure in targeted ErbB2 anticancer therapy.
In this review, we address clinical aspects and mechanisms of ventricular dysfunction induced by anticancer drugs targeted to the ErbB2 receptor. ErbB2 antagonists prolong survival in cancer, but also interfere with homeostatic processes in the heart. ErbB2 is a coreceptor for ErbB4, which is activated by neuregulin-1. ⋯ Differences in the mode of action of individual ErbB2 antagonists affect their impact on the function of the ventricle, considered to be "on-target" or "off-target." Establishing the relation between the cardiac side effects of ErbB2 antagonists and their impact on paracrine ventricular control mechanisms may direct the design of a next generation of ErbB2 inhibitors. For cardiologists, there are lessons to be learned from the unexpected side effects of ErbB2-targeted cancer therapy. The vulnerability of the heart as a pluricellular paracrine system appears greater than anticipated and intercellular crosstalk an essential component of its functional and structural integrity.
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Circulation research · Feb 2008
ReviewPeroxisome proliferator-activated receptor-gamma-mediated effects in the vasculature.
Peroxisome proliferator-activated receptor (PPAR)-gamma is a nuclear receptor and transcription factor in the steroid superfamily. PPAR-gamma agonists, the thiazolidinediones, are clinically used to treat type 2 diabetes. In addition to its function in adipogenesis and increasing insulin sensitivity, PPAR-gamma also plays critical roles in the vasculature. ⋯ Both human genetic studies and animal studies using transgenic mice have demonstrated the importance of PPAR-gamma in these disorders. However, recent clinical studies have raised significant concerns about the cardiovascular side effects of thiazolidinediones, particularly rosiglitazone. Weighing the potential benefit and harm of PPAR-gamma activation and exploring the functional mechanisms may provide a balanced view on the clinical use of these compounds and new approaches to the future therapeutics of vascular disorders associated with diabetes.
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Circulation research · Feb 2008
ReviewThe sulfonylurea receptor, an atypical ATP-binding cassette protein, and its regulation of the KATP channel.
ATP-binding cassette (ABC) proteins are highly conserved and widely expressed throughout nature and found in all organisms, both prokaryotic and eukaryotic. They mediate myriad critical cellular processes, from nutrient import to toxin efflux using the energy derived from ATP hydrolysis. Most ABC proteins mediate transport of substances across lipid membranes. ⋯ K(ATP) is particularly important in the regulation of insulin secretion from pancreatic beta-cells and in regulating action potential duration in muscle cells. SUR is indispensable for normal channel function, and mutations in genes encoding SURs increase the susceptibility to diabetes, myocardial infarction, and heart failure. Here, we review the structure and function of ABC proteins and discuss SUR, its regulation of the K(ATP) channel, and its role in cardiovascular disease.