Sumitra Miriyala

Bone Morphogenic Protein-4 Induces Hypertension in Mice Role of Noggin, Vascular NADPH Oxidases, and Impaired Vasorelaxation

Background— Recent in vitro studies have shown that disturbed flow and oxidative conditions induce the expression of bone morphogenic proteins (BMPs 2 and 4) in cultured endothelial cells. BMPs can stimulate superoxide production and inflammatory responses in endothelial cells, raising the possibility that BMPs may play a role in vascular diseases such as hypertension and atherosclerosis. In this study, we examined the hypothesis that BMP4 would induce hypertension in intact animals by increasing superoxide production from vascular nicotinamide adenine dinucleotide phosphate (NADPH) oxidases and an impairment of vasodilation responses. Methods and Results— BMP4 infusion by osmotic pumps increased systolic blood pressure in a time- and dose-dependent manner in both C57BL/6 mice (from 101 to 125 mm Hg) and apolipoprotein E–null mice (from 107 to 146 mm Hg) after 4 weeks. Cotreatment with the BMP antagonist noggin or the NADPH oxidase inhibitor apocynin completely blocked the BMP4 effect. In addition, BMP4 infusion stimulated aortic NADPH oxidase activity and impaired vasorelaxation, both of which were prevented either by coinfusing noggin or by treating the isolated aortas with apocynin. BMP4, however, did not cause significant changes in maximum relaxation induced by the endothelium-independent vasodilator nitroglycerin. Remarkably, BMP4 infusion failed to stimulate aortic NADPH oxidases, increase blood pressure, and impair vasodilation responses in p47phox-deficient mice. Conclusions— These results suggest that BMP4 infusion induces hypertension in mice in a vascular NADPH oxidase–dependent manner and the subsequent endothelial dysfunction. We suggest that BMP4 is a novel mediator of endothelial dysfunction and hypertension and that noggin and its analogs could be used as therapeutic agents for treating vascular diseases.

PPARγ and Its Role in Cardiovascular Diseases

Peroxisome proliferator-activated receptor Gamma (PPARγ), a ligand-activated transcription factor, has a role in various cellular functions as well as glucose homeostasis, lipid metabolism, and prevention of oxidative stress. The activators of PPARγ are already widely used in the treatment of diabetes mellitus. The cardioprotective effect of PPARγ activation has been studied extensively over the years making them potential therapeutic targets in diseases associated with cardiovascular disorders. However, they are also associated with adverse cardiovascular events such as congestive heart failure and myocardial infarction. This review aims to discuss the role of PPARγ in the various cardiovascular diseases and summarize the current knowledge on PPARγ agonists from multiple clinical trials. Finally, we also review the new PPARγ agonists under development as potential therapeutics with reduced or no adverse effects.

UCP2 overexpression enhanced glycolysis via activation of PFKFB2 during skin cell transformation

Uncoupling protein 2 (UCP2) is an inner mitochondrial membrane transporter which is often upregulated in human cancers. However, how this anion transporter affects tumorigenesis is not well understood. Using the skin cell transformation JB6 model, we demonstrated that UCP2 overexpression activated phosphofructokinase 2/fructose-2,6-bisphosphatase 2 (PFKFB2), a key regulator of glycolysis. In conjunction, upregulation of PFKFB2 expression correlated with elevated fructose 2,6-bisphosphate (Fru-2,6-P2) levels, 6-phosphofructo-1-kinase (PFK-1) activity, glucose uptake, and lactate production. Inhibiting PFKFB2 expression suppressed UCP2-mediated skin cell transformation, decreased cell proliferation, and enhanced mitochondrial respiration, while dampening aerobic glycolysis. The AKT signaling pathway was activated in the UCP2 overexpressed cells; furthermore, the activated AKT signaling contributed to the activation of PFKFB2. Whereas AKT inactivation blocked PFKFB2 activation, suggesting that AKT activation is an important step in PFKFB2 activation. Collectively, our data suggest that UCP2 is a critical regulator of cellular metabolism during cell transformation. Our data also demonstrate a potentially novel mechanism to understand UCP2s tumor-promoting role, which is through the AKT-dependent activation of PFKFB2 and thereby, the metabolic shift to glycolysis (the Warburg effect).

Biomarkers in ROS and Role of Isoprostanes in Oxidative Stress

Biomarkers of reactive oxygen species serve as indicators of oxidative stress in the pathology of cardiovascular diseases. This chapter presents an overview of the various biomarkers available to quantify oxidative stress to advance the understanding of the pathophysiology of cardiovascular diseases as well as to serve as an adjunct in their diagnosis and prognosis. The plasma levels of reactive oxygen species themselves are unstable and unreliable markers of oxidative stress. The commonly used stable biomarkers are derivatives of oxygen radicals such as products of lipid peroxidation and protein oxidation, with isoprostanes and malondialdehyde (MDA) being the most widely used biomarkers due to higher specificity and ease of measurement. Recently, micro‐RNA is emerging as stable and specific biomarkers for detection of heart failure. Other biomarkers have a role in certain conditions; for example, advanced oxidation protein products indicate acute inflammation, whereas advanced glycation end products serve as indicators of chronic disease.