Evaluation of Immunomodulatory Biomarkers in a Pressure Overload Model of Heart Failure

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90380/1/phco.27.4.504.pd

Effects of Hawthorn on the Progression of Heart Failure in a Rat Model of Aortic Constriction

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90301/1/phco.29.6.639.pd

Studies of Prevention, Treatment and Mechanisms of Heart Failure in the Aging Spontaneously Hypertensive Rat

The spontaneously hypertensive rat (SHR) is an animal model of genetic hypertension which develops heart failure with aging, similar to man. The consistent pattern of a long period of stable hypertrophy followed by a transition to failure provides a useful model to study mechanisms of heart failure with aging and test treatments at differing phases of the disease process. The transition from compensated hypertrophy to failure is accompanied by changes in cardiac function which are associated with altered active and passive mechanical properties of myocardial tissue; these events define the physiologic basis for cardiac decompensation. In examining the mechanism for myocardial tissue dysfunction, studies have demonstrated a central role for neurohormonal activation, and specifically the renin-angiotensin-aldosterone system. Pharmacologic attenuation of this system at differing points in the course of the process suggests that prevention but not reversal of myocardial tissue dysfunction is possible. The roles of the extracellular matrix, apoptosis, intracellular calcium, beta-adrenergic stimulation, microtubules, and oxygen supply-demand relationships in ultimately mediating myocardial tissue dysfunction are reviewed. Studies suggest that while considerable progress has been made in understanding and treating the transition to failure, our current state of knowledge is limited in scope and we are not yet able to define specific mechanisms responsible for tissue dysfunction. It will be necessary to integrate information on the roles of newly discovered, and as yet undiscovered, genes and pathways to provide a clearer understanding of maladaptive remodeling seen with heart failure. Understanding the mechanism for tissue dysfunction is likely to result in more effective treatments for the prevention and reversal of heart failure with aging. It is anticipated that the SHR model will assist us in reaching these important goals.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45828/1/10741_2004_Article_391524.pd

The mTOR/p70 S6K Signal Transduction Pathway Plays a Role in Cardiac Hypertrophy and Influences Expression of Myosin Heavy Chain Genes in vivo

Objective: Rapamycin (R) inhibits p70 S6 kinase (p70 S6K ) activity and hypertrophy of cultured neonatal rat cardiac myocytes. The purpose of the present study was to determine whether rapamycin inhibits left ventricular (L V) hypertrophy in intact rats and whether it alters cardiac gene expression.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44579/1/10557_2004_Article_5277209.pd

Self-organization of rat cardiac cells into contractile 3-D cardiac tissue

The mammalian heart is not known to regenerate following injury. Therefore, there is great interest in developing viable tissue‐based models for cardiac assist. Recent years have brought numerous advances in the development of scaffold‐based models of cardiac tissue, but a self‐organizing model has yet to be described. Here, we report the development of an in vitro cardiac tissue without scaffolding materials in the contractile region. Using an optimal concentration of the adhesion molecule laminin, a confluent layer of neonatal rat cardiomyogenic cells can be induced to self‐organize into a cylindrical construct, resembling a papillary muscle, which we have termed a cardioid. Like endogenous heart tissue, cardioids contract spontaneously and can be electrically paced between 1 and 5 Hz indefinitely without fatigue. These engineered cardiac tissues also show an increased rate of spontaneous contraction (chronotropy), increased rate of relaxation (lusitropy), and increased force production (inotropy) in response to epinephrine. Cardioids have a developmental protein phenotype that expresses both α‐ and β‐tropomyosin, very low levels of SERCA2a, and very little of the mature isoform of cardiac troponin T.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154481/1/fsb2fj042034fje-sup-0001.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154481/2/fsb2fj042034fje.pd

Changes in the rat heart proteome induced by exercise training: Increased abundance of heat shock protein hsp20

Chronic exercise training elicits adaptations in the heart that improve pump function and confer cardioprotection. To identify molecular mechanisms by which exercise training stimulates this favorable phenotype, a proteomic approach was employed to detect rat cardiac proteins that were differentially expressed or modified after exercise training. Exercise-trained rats underwent six weeks of progressive treadmill training five days/week, 0% 14grade, using an interval training protocol. Sedentary control rats were age- and weight-matched to the exercise-trained rats. Hearts were harvested at various times (0–72 14h) after the last bout of exercise and were used to generate 2-D electrophoretic proteome maps and immunoblots. Compared with hearts of sedentary rats, 26 14protein spot intensities were significantly altered in hypertrophied hearts of exercise-trained rats ( p  14<0.05), and 12 14spots appeared exclusively on gels from hearts of exercise-trained rats. Immunoblotting confirmed that chronic exercise training, but not a single bout of exercise, elicited a ˜2.5-fold increase in the abundance of one of the candidate proteins in the heart, a ˜20 14kDa heat shock protein (hsp20) that persisted for at least 72 14h of detraining. Thus, exercise training alters the cardiac proteome of the rat heart; the changes include a marked increase in the expression of hsp20.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/50684/1/3154_ftp.pd

Enhanced Expression of p53 and Apoptosis Induced by Blockade of the Vacuolar Proton ATPase in Cardiomyocytes

Activation of the vacuolar proton ATPase (VPATPase) has been implicated in the prevention of apoptosis in neutrophils and adult cardiac myocytes. To determine the role of the VPATPase in apoptosis of cardiac myocytes, we used a potent and specific inhibitor of the VPATPase, bafilomycin A1. Bafilomycin A1 alone caused increased DNA laddering of genomic DNA and increased nuclear staining for fragmented DNA in neonatal cardiomyocyte apoptosis in a dose- and time-dependent manner. Intracellular acidification in cardiac myocytes was also observed after 18 h of bafilomycin A1 treatment. Accordingly, bafilomycin A1–treated myocytes also showed increased accumulation of p53 protein and p53-dependent transactivation of gene expression, including a persistent upregulation of p21/wild-type p53 activated fragment 1/cyclin kinase inhibitor protein-1 mRNA. The bafilomycin A1–induced increase in p53 protein levels was accompanied by a marked increase in p53 mRNA accumulation. In contrast, cardiac fibroblasts treated with bafilomycin A1 showed no change in p53 protein expression or pH i and did not undergo apoptosis even after 24 h of treatment. Our data suggest that blockade of the VPATPase induces apoptotic cell death of cardiac myocytes and that this may occur through a p53-mediated apoptotic pathway