Physiology Commons^™

Calpain Inhibition Attenuates Adipose Tissue Inflammation And Fibrosis In Diet-Induced Obese Mice, Latha Muniappan, Aida Javidan, Weihua Jiang, Shayan Mohammadmoradi, Jessica J. Moorleghen, Wendy S. Katz, Anju Balakrishnan, Deborah A. Howatt, Venkateswaran Subramanian

Saha Cardiovascular Research Center Faculty Publications

Adipose tissue macrophages have been proposed as a link between obesity and insulin resistance. However, the mechanisms underlying these processes are not completely defined. Calpains are calcium-dependent neutral cysteine proteases that modulate cellular function and have been implicated in various inflammatory diseases. To define whether activated calpains influence diet-induced obesity and adipose tissue macrophage accumulation, mice that were either wild type (WT) or overexpressing calpastatin (CAST Tg), the endogenous inhibitor of calpains were fed with high (60% kcal) fat diet for 16 weeks. CAST overexpression did not influence high fat diet-induced body weight and fat mass gain throughout the study. …

Deletion Of The Nr4a Nuclear Receptor Nor1 In Hematopoietic Stem Cells Reduces Inflammation But Not Abdominal Aortic Aneurysm Formation, Hua Qing, Karrie L. Jones, Elizabeth B. Heywood, Hong Lu, Alan Daugherty, Dennis Bruemmer

Pharmacology and Nutritional Sciences Faculty Publications

Background: The NR4A3 orphan nuclear hormone receptor, NOR1, functions as a constitutively active transcription factor to regulate inflammation, proliferation, and cell survival during pathological vascular remodeling. Inflammatory processes represent key mechanisms leading to abdominal aortic aneurysm (AAA) formation. However, a role of NOR1 in AAA formation has not been investigated previously.

Methods: Inflammatory gene expression was analyzed in bone marrow-derived macrophages isolated from NOR1-deficient mice. Low-density lipoprotein receptor-deficient (LDLr^−/−) mice were irradiated and reconstituted with hematopoietic stem cells obtained from NOR1−/− or wild-type littermate mice. Animals were infused with angiotensin II and fed a diet enriched in saturated …

No Difference In Myosin Kinetics And Spatial Distribution Of The Lever Arm In The Left And Right Ventricles Of Human Hearts, Divya Duggal, S. Requena, Janhavi Nagwekar, Sangram Raut, Ryan Rich, Hriday Das, Vipul Patel, Ignacy Gryczynski, Rafal Fudala, Zygmunt Gryczynski, Cheavar Blair, Kenneth S. Campbell, Julian Borejdo

Physiology Faculty Publications

The systemic circulation offers larger resistance to the blood flow than the pulmonary system. Consequently, the left ventricle (LV) must pump blood with more force than the right ventricle (RV). The question arises whether the stronger pumping action of the LV is due to a more efficient action of left ventricular myosin, or whether it is due to the morphological differences between ventricles. Such a question cannot be answered by studying the entire ventricles or myocytes because any observed differences would be wiped out by averaging the information obtained from trillions of myosin molecules present in a ventricle or myocyte. …

Body Size Predicts Cardiac And Vascular Resistance Effects On Men's And Women's Blood Pressure, Joyce M. Evans, Siqi Wang, Christopher Greb, Vladimir Kostas, Charles F. Knapp, Qingguang Zhang, Eric S. Roemmele, Michael B. Stenger, David C. Randall

Biomedical Engineering Faculty Publications

Key Points Summary

• We report how blood pressure, cardiac output and vascular resistance are related to height, weight, body surface area (BSA), and body mass index (BMI) in healthy young adults at supine rest and standing.
• Much inter-subject variability in young adult's blood pressure, currently attributed to health status, may actually result from inter-individual body size differences.
• Each cardiovascular variable is linearly related to height, weight and/or BSA (more than to BMI).
• When supine, cardiac output is positively related, while vascular resistance is negatively related, to body size. Upon standing, the change in vascular resistance is positively related to size. …

Qt Prolongation Is Associated With Increased Mortality In End Stage Liver Disease, Sun Moon Kim, Bennet George, Diego Alcivar-Franco, Charles L. Campbell, Richard Charnigo, Brian P. Delisle, Jonathan Hundley, Yousef Darrat, Gustavo Morales, Samy-Claude Elayi, Alison L. Bailey

Internal Medicine Faculty Publications

AIM

To determine the prevalence of QT prolongation in a large series of end stage liver disease (ESLD) patients and its association to clinical variables and mortality.

METHODS

The QT interval was measured and corrected for heart rate for each patient, with a prolonged QT cutoff defined as QT > 450 ms for males and QT > 470 ms for females. Multiple clinical variables were evaluated including sex, age, serum sodium, international normalized ratio, creatinine, total bilirubin, beta-blocker use, Model for End-Stage Liver Disease (MELD), MELD-Na, and etiology of liver disease.

RESULTS

Among 406 ESLD patients analyzed, 207 (51.0%) had QT prolongation. …

Myocardial Relaxation Is Accelerated By Fast Stretch, Not Reduced Afterload, Charles S. Chung, Charles W. Hoopes, Kenneth S. Campbell

Physiology Faculty Publications

Fast relaxation of cross-bridge generated force in the myocardium facilitates efficient diastolic function. Recently published research studying mechanisms that modulate the relaxation rate has focused on molecular factors. Mechanical factors have received less attention since the 1980s when seminal work established the theory that reducing afterload accelerates the relaxation rate. Clinical trials using afterload reducing drugs, partially based on this theory, have thus far failed to improve outcomes for patients with diastolic dysfunction. Therefore, we reevaluated the protocols that suggest reducing afterload accelerates the relaxation rate and identified that myocardial relengthening was a potential confounding factor. We hypothesized that the …

Omecamtiv Mecarbil Enhances The Duty Ratio Of Human Β-Cardiac Myosin Resulting In Increased Calcium Sensitivity And Slowed Force Development In Cardiac Muscle, Anja M. Swenson, Wanjian Tang, Cheavar A. Blair, Christopher M. Fetrow, William C. Unrath, Michael J. Previs, Kenneth S. Campbell, Christopher M. Yengo

Physiology Faculty Publications

The small molecule drug omecamtiv mecarbil (OM) specifically targets cardiac muscle myosin and is known to enhance cardiac muscle performance, yet its impact on human cardiac myosin motor function is unclear. We expressed and purified human β-cardiac myosin subfragment 1 (M2β-S1) containing a C-terminal Avi tag. We demonstrate that the maximum actin-activated ATPase activity of M2β-S1 is slowed more than 4-fold in the presence of OM, whereas the actin concentration required for half-maximal ATPase was reduced dramatically (30-fold). We find OM does not change the overall actin affinity. Transient kinetic experiments suggest that there are …