Txnip ablation reduces vascular smooth muscle cell inflammation and ameliorates atherosclerosis in apolipoprotein E knockout mice.

Objective: Inflammation of vascular smooth muscle cells (VSMC) is intimately linked to atherosclerosis and other vascular inflammatory disease. Thioredoxin interacting protein (Txnip) is a key regulator of cellular sulfhydryl redox and a mediator of inflammasome activation. The goals of the present study were to examine the impact of Txnip ablation on inflammatory response to oxidative stress in VSMC and to determine the effect of Txnip ablation on atherosclerosis in vivo.

Myocardial function with reduced expression of the sodium-calcium exchanger.

Background: The complete removal of the cardiac sodium-calcium exchanger (NCX1) is associated with embryonic lethality, whereas its overexpression is linked to heart failure. To determine whether or not a reduced expression of NCX1 is compatible with normal heart structure and function, we studied 2 knockout (KO) mouse models with reduced levels of NCX1: a heterozygous global KO (HG-KO) with a 50% level of NCX1 expression in all myocytes, and a ventricular-specific KO (V-KO) with NCX1 expression in only 10% to 20% of the myocytes.

Methods And Results: Both groups of mice were evaluated at baseline, after transaortic constriction (TAC), and after acute or chronic beta-adrenergic stimulation.

Hypertrophy and heart failure in mice overexpressing the cardiac sodium-calcium exchanger.

Background: The cardiac sodium-calcium exchanger (NCX1) is a key sarcolemmal protein for the maintenance of calcium homeostasis in the heart. Because heart failure is associated with increased expression of NCX1, heterozygous (HET) and homozygous (HOM) transgenic mice overexpressing NCX1 were developed and evaluated.

Methods And Results: The NCX1 transgenic mice display 2.

Functional adult myocardium in the absence of Na+-Ca2+ exchange: cardiac-specific knockout of NCX1.

The excitation-contraction coupling cycle in cardiac muscle is initiated by an influx of Ca2+ through voltage-dependent Ca2+ channels. Ca2+ influx induces a release of Ca2+ from the sarcoplasmic reticulum and myocyte contraction. To maintain Ca2+ homeostasis, Ca2+ entry is balanced by efflux mediated by the sarcolemmal Na+-Ca2+ exchanger.

Overexpression of glucosylceramide synthase and P-glycoprotein in cancer cells selected for resistance to natural product chemotherapy.

Resistance to natural product chemotherapy drugs is a major obstacle to successful cancer treatment. This type of resistance is often acquired in response to drug exposure; however, the mechanisms of this adverse reaction are complex and elusive. Here, we have studied acquired resistance to Adriamycin, Vinca alkaloids, and etoposide in MCF-7 breast cancer cells, KB-3-1 epidermoid carcinoma cells, and other cancer cell lines to determine if there is an association between expression of glucosylceramide synthase, the enzyme catalyzing ceramide glycosylation to glucosylceramide, and the multidrug-resistant (MDR) phenotype.

Mice overexpressing the cardiac sodium-calcium exchanger: defects in excitation-contraction coupling.

Homozygous overexpression of the cardiac Na(+)-Ca(2+) exchanger causes cardiac hypertrophy and increases susceptibility to heart failure in response to stress. We studied the functional effects of homozygous overexpression of the exchanger at the cellular level in isolated mouse ventricular myocytes. Compared with patch-clamped myocytes from wild-type animals, non-failing myocytes from homozygous transgenic mice exhibited increased cell capacitance (from 208 +/- 16 pF to 260 +/- 15 pF, P < 0.

Cardiac excitation-contraction coupling in the absence of Na(+) - Ca2+ exchange.

We investigate cardiac excitation-contraction coupling in the absence of sarcolemmal Na(+) - Ca(2+) exchange using NCX1 knock out mice. Knock out of NCX1 is embryonic lethal, and we measure Ca(2+) transients and contractions in heart tubes from embryos at day 9.5 post coitum.

Knockout mice for pharmacological screening: testing the specificity of Na+-Ca2+ exchange inhibitors.

The role of the Na+-Ca2+ exchanger as a major determinant of cell Ca2+ is well defined in cardiac tissue, and there has been much effort to develop specific inhibitors of the exchanger. We use a novel system to test the specificity of two putative specific inhibitors, KB-R7943 and SEA0400. The drugs are applied to electrically stimulated heart tubes from control mouse embryos or embryos with the Na+-Ca2+ exchanger knocked out.

The Na+-Ca2+ exchanger is essential for the action of cardiac glycosides.

The widely accepted model to explain the positive inotropic effect of cardiac glycosides invokes altered Na+-Ca2+ exchange activity secondary to Na+ pump inhibition. However, proof of this model is lacking and alternative mechanisms have been proposed. We directly tested the role of the Na+-Ca2+ exchanger in the action of the glycoside ouabain using Na+-Ca2+ exchanger knockout mice.