Kit for Detecting CTHRC1 in a Sample

The invention provides methods for the treatment of coronary heart disease, peripheral vascular disease, stroke, and ischemia featuring agents that interfere with the expression or activity of Cthrc1. The invention also provides the use of Cthrc1 peptide as a therapeutic agent for the treatment of acute or chronic cardiac deficiencies. The invention further provides detection and monitoring of Cthrc1 peptide in blood or serum to assess or monitor cardiac function

Thyroid Hormone-Clearing Deiodinase 3 Protects from Cranio- Encephalic and Cardiac Congenital Abnormalities

Implications: Transient overexposure to TH during development may contribute to idiopathic congenital syndromes in humans (cleft palate, hydrocephalus, cardiac and Chiari malformations, others)https://knowledgeconnection.mainehealth.org/lambrew-retreat-2021/1054/thumbnail.jp

Conditional expression of Spry1 in neural crest causes craniofacial and cardiac defects

<p>Abstract</p> <p>Background</p> <p>Growth factors and their receptors are mediators of organogenesis and must be tightly regulated in a temporal and spatial manner for proper tissue morphogenesis. Intracellular regulators of growth factor signaling pathways provide an additional level of control. Members of the Sprouty family negatively regulate receptor tyrosine kinase pathways in several developmental contexts. To gain insight into the role of Spry1 in neural crest development, we analyzed the developmental effects of conditional expression of Spry1 in neural crest-derived tissues.</p> <p>Results</p> <p>Here we report that conditional expression of Spry1 in neural crest cells causes defects in craniofacial and cardiac development in mice. <it>Spry1;Wnt1-Cre </it>embryos die perinatally and exhibit facial clefting, cleft palate, cardiac and cranial nerve defects. These defects appear to be the result of decreased proliferation and increased apoptosis of neural crest and neural crest-derived cell populations. In addition, the domains of expression of several key transcription factors important to normal craniofacial and cardiac development including <it>AP2</it>, <it>Msx2</it>, <it>Dlx5</it>, and <it>Dlx6 </it>were reduced in <it>Spry1;Wnt1-Cre </it>transgenic embryos.</p> <p>Conclusion</p> <p>Collectively, these data suggest that Spry1 is an important regulator of craniofacial and cardiac morphogenesis and perturbations in Spry1 levels may contribute to congenital disorders involving tissues of neural crest origin.</p

Palmitate diet-induced loss of cardiac caveolin-3: a novel mechanism for lipid-induced contractile dysfunction.

Obesity is associated with an increased risk of cardiomyopathy, and mechanisms linking the underlying risk and dietary factors are not well understood. We tested the hypothesis that dietary intake of saturated fat increases the levels of sphingolipids, namely ceramide and sphingomyelin in cardiac cell membranes that disrupt caveolae, specialized membrane micro-domains and important for cellular signaling. C57BL/6 mice were fed two high-fat diets: palmitate diet (21% total fat, 47% is palmitate), and MCT diet (21% medium-chain triglycerides, no palmitate). We established that high-palmitate feeding for 12 weeks leads to 40% and 50% increases in ceramide and sphingomyelin, respectively, in cellular membranes. Concomitant with sphingolipid accumulation, we observed a 40% reduction in systolic contractile performance. To explore the relationship of increased sphingolipids with caveolins, we analyzed caveolin protein levels and intracellular localization in isolated cardiomyocytes. In normal cardiomyocytes, caveolin-1 and caveolin-3 co-localize at the plasma membrane and the T-tubule system. However, mice maintained on palmitate lost 80% of caveolin-3, mainly from the T-tubule system. Mice maintained on MCT diet had a 90% reduction in caveolin-1. These data show that caveolin isoforms are sensitive to the lipid environment. These data are further supported by similar findings in human cardiac tissue samples from non-obese, obese, non-obese cardiomyopathic, and obese cardiomyopathic patients. To further elucidate the contractile dysfunction associated with the loss of caveolin-3, we determined the localization of the ryanodine receptor and found lower expression and loss of the striated appearance of this protein. We suggest that palmitate-induced loss of caveolin-3 results in cardiac contractile dysfunction via a defect in calcium-induced calcium release

Decreased energetics in murine hearts bearing the R92Q mutation in cardiac troponin T

The thin filament protein cardiac troponin T (cTnT) is an important regulator of myofilament activation. Here we report a significant change in cardiac energetics in transgenic mice bearing the missense mutation R92Q within the tropomyosin-binding domain of cTnT, a mutation associated with a clinically severe form of familial hypertrophic cardiomyopathy. This functional domain of cTnT has recently been shown to be a crucial modulator of contractile function despite the fact that it does not directly interact with the ATP hydrolysis site in the myosin head. Simultaneous measurements of cardiac energetics using (31)P NMR spectroscopy and contractile performance of the intact beating heart revealed both a decrease in the free energy of ATP hydrolysis available to support contractile work and a marked inability to increase contractile performance upon acute inotropic challenge in hearts from R92Q mice. These results show that alterations in thin filament protein structure and function can lead to significant defects in myocardial energetics and contractile reserve

Palmitate-induced loss of T-tubular caveolin-3 and loss of striated appearance of the RyR localization.

<p>Intracellular localization of caveolin-1 (<b>A</b>) or caveolin-3 (<b>B</b>) and RyR in isolated cardiomyocytes from standard, MCT or palmitate diet fed mice. Caveolin-1 and -3 localize to the plasma membrane and the T-tubule system in standard diet fed mice (first row of panels in A and B). In MCT diet fed mice caveolin-1 expression decreases (second row of panels in A) but caveolin-3 expression remains unchanged (second row of panels in B). MCT diet does not change the striated appearance of the RyR (compare both middle panels in A and B). Palmitate diet does not change the expression or localization of caveolin-1 (third row panel A), but expression of caveolin-3 decreases and it is absent from the T-tubule system. In these areas the striated appearance of the RyR is lost (arrows in A and B). All confocal experiments were repeated at least 4 times with similar results.</p

Loss of vitamin A stores impairs cardiac workload and function under stress conditions

Study Objectives: Assess cardiac function under baseline and cardiac stress conditions in mice with and without hepatic vitamin A stores

Caveolin-3 expression is decreased in obese human cardiac LV tissue.

<p>Representative immunohistochemistry showing caveolin-3 in normal, obese, obese with cardiomyopathy, and non-obese cardiomyopathy human left ventricular cardiac tissue. In normal human cardiomyocytes (upper left panel) caveolin-3 is expressed at the plasma membrane and the T-tubule system (white arrows). In obesity (lower left panel), the expression of caveolin-3 is drastically decreased in the T-tubule system (black arrows), which can occur independent of associated heart disease as the samples with cardiomyopathy (upper right panel) show, but seem to be enhanced in obese cases with cardiomyopathy (lower right panel).</p

Dietary intervention is sufficient to reverse palmitate-induced caveolin-3 loss.

<p><b>A</b>) Western blots of cardiac tissue of mice maintained on standard, MCT, or palmitate diet for 12 weeks followed by 12 weeks of standard laboratory chow feeding. Caveolin-1 and -3 expression is normal. (Std standard, MCT medium chain triglyceride high fat control diet, P palmitate). <b>B</b>) Ex vivo contractile performance (RPP, pdP/dt and ndP/dt) and calcium sensitivity normalizes after 12 weeks of standard laboratory chow feeding. N = 6 (3 male and 3 female) per diet, linear regression analysis is not significant.</p