Melissa R. Dent

Subcellular Remodeling as a Viable Target for the Treatment of Congestive Heart Failure

It is now well known that congestive heart failure (CHF) is invariably associated with cardiac hypertrophy, and changes in the shape and size of cardiomyocytes (cardiac remodeling) are considered to explain cardiac dysfunction in CHF. However, the mechanisms responsible for the transition of cardiac hypertrophy to heart failure are poorly understood. Several lines of evidence both from various experimental models of CHF and from patients with different types of CHF have indicated that the functions of different subcellular organelles such as extracellular matrix, sarcolemma, sarcoplasmic reticulum, myofibrils, mitochondria, and nucleus are defective. Subcellular abnormalities for protein contents, gene expression, and enzyme activities in the failing heart become evident as a consequence of prolonged hormonal imbalance, metabolic derangements, and cation maldistribution. In particular, the occurrence of oxidative stress, development of intracellular Ca2+ overload, activation of proteases and phospholipases, and alterations in cardiac gene expression result in changes in the biochemical composition, molecular structure, and function of different subcellular organelles (subcellular remodeling). Not only does subcellular remodeling appear to be intimately involved in the transition of cardiac hypertrophy to heart failure, the mismatching of the function of different subcellular organelles leads to the development of cardiac dysfunction. Although blockade of the renin-angiotensin system, sympathetic nervous system, and various other hormonal actions have been reported to produce beneficial effects on cardiac remodeling and heart dysfunction in CHF, the actions of various cardiac drugs on subcellular remodeling have not been examined extensively. Some recent studies have indicated that both the angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists attenuate changes in sarcolemma, sarcoplasmic reticulum, and myofibril enzyme activities, protein contents, and gene expression, and partly improve cardiac function in the failing hearts. It is suggested that subcellular remodeling is an excellent target for the development of improved drug therapy for CHF. Furthermore, extensive studies should investigate the effects of different agents individually or in combination on reverse subcellular remodeling, cardiac remodeling, and cardiac dysfunction in various experimental models of CHF.

Gender differences in apoptotic signaling in heart failure due to volume overload

This study examined sex differences in the regulation of pro- and anti-apoptotic proteins in cardiac hypertrophy and heart failure due to volume overload induced by arteriovenous (AV) shunt in rats. General characteristics and hemodynamic assessment revealed the presence of cardiac hypertrophy at 4xa0weeks of AV shunt in male (nxa0=xa012) and female (nxa0=xa012) rats, whereas heart failure was seen at 16xa0weeks in male rats only. Although a decrease in apoptosis was seen in hearts of both sexes at 4xa0weeks, an increase in apoptosis in males and a reduction in the female heart were observed at 16xa0weeks of AV shunt. Unlike females, increases in the pro-apoptotic proteins, BAX, caspases 3 and 9 were seen in 16xa0weeks post-AV shunt in male rats. While an increase in phospho-Bad was detected, phospho-Bcl-2 protein was decreased in males. Females showed an increase in only phospho-Bcl-2 protein at 16xa0weeks post-AV shunt. Ovariectomy (nxa0=xa012) abolished the increase in phospho-Bcl-2 protein, but this was restored by treatment with 17-β estradiol. These data suggest that downregulation of phospho-Bcl-2 and an upregulation of BAX may play a major role in cardiomyocyte apoptosis in heart failure due to volume overload in male rats. Furthermore, upregulation of phospho-Bcl-2 in the heart due to estrogen may confer resistance against cardiomyocyte apoptosis in females.

Expression of phospholipase D isozymes in scar and viable tissue in congestive heart failure due to myocardial infarction.

The phospholipase D (PLD) associated with the cardiac sarcolemmal (SL) membrane hydrolyses phosphatidylcholine to produce phosphatidic acid, an important phospholipid signaling molecule known to influence cardiac function. The present study was undertaken to examine PLD isozyme mRNA expression, protein contents and activities in congestive heart failure (CHF) subsequent to myocardial infarction (MI). MI was induced in rats by occlusion of the left anterior descending coronary artery. At 8 weeks after the surgical procedure, hemodynamic assessment revealed that these experimental rats were at a moderate stage of CHF. Semi‐quantitative reverse transcriptase‐polymerase chain reaction revealed that PLD1 and PLD2 mRNA amounts were unchanged in viable left ventricular (LV) tissue of the failing heart. Furthermore, this technique demonstrated the presence of PLD1 and PLD2 mRNA in the scar tissue. While SL PLD1 and PLD2 protein contents were elevated in the viable LV tissue of the failing heart, SL PLD1 activity was significantly decreased, whereas SL PLD2 activity was significantly increased. On the other hand, although PLD1 protein was undetectable, PLD2 protein and activity were detected in the scar tissue. Our findings suggest that differential changes in PLD isozymes may contribute to the pathophysiology of CHF and may also be involved in the processes of scar remodeling.

Gender differences in β-adrenoceptor system in cardiac hypertrophy due to arteriovenous fistula

This study was undertaken to determine alterations in the β‐adrenoceptor (β‐AR) signaling system in male and female rats at 4 weeks after the induction of arteriovenous (AV) fistula or shunt. AV shunt produced a greater degree of cardiac hypertrophy and larger increase in cardiac output in male than in female animals. Increases in plasma levels of norepinephrine and epinephrine (EPI) due to AV shunt were also higher in male than females. While no difference in the β1‐AR affinity was seen in males and females, AV shunt induced increase in β1‐AR density in female rats was higher than that in males. Furthermore, no changes in basal adenylyl cyclase (AC) V/VI mRNA levels were seen; however, the increase in EPI‐stimulated AC activities was greater in AV shunt females than in males. AV shunt decreased myocardial β1‐AR mRNA level in male rats and increased β2‐AR mRNA level in female hearts; an increase in Gi‐protein mRNA was detected only in male hearts. Although GRK2 gene expression was increased in both sexes, an increase in GRK3 mRNA was seen only in AV shunt female rats. β‐arrestin1 mRNA was elevated in females whereas β‐arrestin 2 gene expression was increased in both male and female AV shunt rats. While these data demonstrate gender associated differences in various components of the β‐AR system in cardiac hypertrophy due to AV shunt, only higher levels of plasma catecholamines may account for the greater increase in cardiac output and higher degree of cardiac hypertrophy in males. J. Cell. Physiol. 226: 181–186, 2010.

Gender differences in the modulation of cardiac gene expression by dietary conjugated linoleic acid isomersThis paper is one of a selection of papers published in this Special Issue, entitled The Cellular and Molecular Basis of Cardiovascular Dysfunction, Dhalla 70th Birthday Tribute.

In an earlier study, we showed that dietary conjugated linoleic acid (CLA) isomers can exert differential effects on heart function in male and female rats, but the underlying mechanisms for these actions are not known. Cardiomyocyte Ca2+ cycling is a key event in normal cardiac contractile function and defects in Ca2+ cycling are associated with cardiac dysfunction and heart disease. We therefore hypothesized that abnormalities in the sarcolemmal (SL) and sarcoplasmic reticulum (SR)-mediated regulation of intracellular Ca2+ contribute to altered cardiac contractile function of male and female rats owing to dietary CLA isomers. Healthy male and female Sprague-Dawley rats were fed different CLA isomers, (cis-9, trans-11 (c9,t11) and trans-10, cis-12 (t10,c12)) individually and in combination (50:50 mix as triglyceride or fatty acids) from 4 to 20 weeks of age. We determined the mRNA levels of sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) 2a, ryanodine receptor, phospholamban, calsequestrin, Na+-Ca2+-exchanger (NCX), and L-type Ca2+ channel in the left ventricle (LV) by RT-PCR. The SR function was assessed by measurement of Ca2+-uptake and -release. Significant gender differences were seen in the LV NCX, L-type Ca2+ channel, and ryanodine receptor mRNA expression levels in control male and female rats. Dietary CLA isomers in the various forms induced changes in the mRNA levels of SERCA 2a, NCX, and L-type Ca2+ channel in the LV of both male and female hearts. Whereas protein contents of the Ca2+ cycling proteins were altered, changes in SR Ca2+-uptake and -release were also detected in both male and female rats in response to dietary CLA. The results of this study demonstrate that long-term dietary supplementation can modulate cardiac gene expression and SR function in a gender-related manner and may, in part, contribute to altered cardiac contractility.

Phospholipid-mediated signaling in diseased myocardium

Myocardial phospholipases hydrolyze specific membrane phospholipids to generate important lipid-signaling molecules that are known to influence cardiac function. It is likely that changes in these phospholipases and their related signaling events may be contributory factors in altering cardiac function in the diseased myocardium. Therefore, identifying the changes in such signaling systems, as well as understanding the contribution of phospholipid-signaling pathways to the pathophysiology of heart disease, are important areas of investigation. This review provides an overview of the rolexa0of phospholipid-mediated signal transduction processes in ischemic heart disease, cardiacxa0hypertrophy and heart failure as well as in diabetic cardiomyopathy. From the evidencexa0provided it is proposed that components of phospholipid-mediated signal transductionxa0processes could serve as novel targets for the treatment of the different types of heartxa0disease.