Left Ventricular Eccentric Remodeling and Matrix Loss Are Mediated by Bradykinin and Precede Cardiomyocyte Elongation in Rats With Volume Overload

Ryan, Thomas; Rothstein, Emily C.; Aban, Inmaculada; Tallaj, José; Husain, Ahsan; Lucchesi, Pamela A.; Dell’Italia, Louis J.

doi:10.1016/j.jacc.2006.06.083

Cited by 121 publications

(172 citation statements)

References 23 publications

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“…A significant increase in myocyte diameter, however, was found in the T2DN mtFHH rats in comparison with T2DN mtWistar . This result coincides with the increase in LV dimensions observed in echocardiographic analysis and is consistent with previous findings that increased cardiomyocyte length is associated with eccentric left ventricular remodeling and dilation (19).Mitochondrial Biogenesis-Slides from two transmission electron microscopy nonserial sections at ϫ8000 and ϫ29,000 magnification were analyzed for mitochondrial number, distribution, and morphology (Fig. 3).…”

supporting

confidence: 90%

Mitochondrial DNA Variant for Complex I Reveals a Role in Diabetic Cardiac Remodeling

Savitha

Vásquez‐Vivar

Migrino

et al. 2012

Journal of Biological Chemistry

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Background: Mitochondrial dysfunction may influence myocardial remodeling in diabetes.Results: Impaired respiratory complex activity and energy depletion without mitochondrial uncoupling was identified in a new conplastic rat model of diabetes. Conclusion: mtDNA mutations are a risk factor for developing myocardial dysfunction in diabetes. Significance: Identifying mtDNA background is important for recognizing patients at risk for heart diseases.Myocardial remodeling and dysfunction are serious complications of type 2 diabetes mellitus (T2DM). Factors controlling their development are not well established. To specifically address the role of the mitochondrial genome, we developed novel conplastic rat strains, i.e. strains with the same nuclear genome but a different mitochondrial genome. The new animals were named T2DN mtFHH and T2DN mtWistar , where the acronym T2DN denotes their common nuclear genome (type 2 diabetic nephropathy (T2DN) rats) and mtFHH or mtWistar the origin of their mitochondria, Fawn Hooded Hypertensive (FHH) or Wistar rats, respectively. The T2DN mtFHH and T2DN mtWistar showed a similar progression of diabetes as determined by HbA1c, cholesterol, and triglycerides with normal blood pressure, thus enabling investigation of the specific role of the mitochondrial genome in cardiac function without the confounding effects of obesity or hypertension found in other models of diabetes. Echocardiographic analysis of 12-week-old animals showed no abnormalities, but at 12 months of age the T2DN mtFHH showed left ventricular remodeling that was verified by histology. Decreased complex I and complex IV but not complex II activity within the electron transport chain was found only in T2DN mtFHH , which was not explained by differences in protein content. Decreased cardiac ATP levels in T2DN mtFHH were in agreement with a lower ATP synthetic capacity by isolated mitochondria. Together, our data provide experimental evidence that mtDNA sequence variations have an additional role in energetic heart deficiency. The mitochondrial DNA background may explain the increased susceptibility of certain T2DM patients to develop myocardial dysfunction. Type 2 diabetes mellitus (T2DM)2 is a complex and heterogeneous disorder with a prevalence nearing epidemic proportions worldwide. Myocardial dysfunction and heart failure are serious complications developing in many cases independently of coronary artery disease and hypertension. It is considered that molecular alterations at the myocyte level may be a key factor in the development of myocardial dysfunction. The pathogenesis of ventricular dysfunction has been examined previously in genetic animal models of T2DM (1-3). Because these models present with a variety of metabolic disorders, it has been impossible to isolate the influence of intrinsic mitochondrial impairments in disease mechanisms.A new rat model of type 2 diabetes mellitus was developed by crossing diabetic male Goto-Kakizaki (GK) rats with female Fawn Hooded Hypertensive (FHH) rats (4). This new T2DM rat ...

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supporting

confidence: 90%

Mitochondrial DNA Variant for Complex I Reveals a Role in Diabetic Cardiac Remodeling

Savitha

Vásquez‐Vivar

Migrino

et al. 2012

Journal of Biological Chemistry

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“…Ruzicka et al used this model for describing renin-angiotensin system and effects of angiotensin converting enzyme inhibitors in situation of volume overload (Ruzicka et al, 1993). Ryan et al described remodeling process induced by bradykinin (Ryan et al, 2007). Study of Hatt et al (1979) is closest to our morphological approach.…”

Section: Discussionmentioning

confidence: 99%

“…Diminished systemic perfusion leads to redistribution of cardiac output and neurohumoral activation. When compensatory mechanisms become inadequate, overt heart failure (HF) develops (Hood et al, 1968) in a way similar to other models of LV hypertrophy-HF transition (Hatt et al, 1979;Legault et al, 1990;Ruzicka et al, 1993;Ryan et al, 2007).…”

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confidence: 96%

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Myocardial Morphological Characteristics and Proarrhythmic Substrate in the Rat Model of Heart Failure Due to Chronic Volume Overload

Beneš

Melenovský

Škaroupková

et al. 2010

The Anatomical Record

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Chronic volume overload leads to cardiac hypertrophy and later to heart failure (HF), which are both associated with increased risk of cardiac arrhythmias. The goal of this study was to describe changes in myocardial morphology and to characterize arrhythmogenic substrate in rat model of developing HF due to volume overload. An arteriovenous fistula (AVF) was created in male Wistar rats between the inferior vena cava and abdominal aorta using needle technique. Myocardial morphology, tissue fibrosis, and connexin43 distribution, localization and phosphorylation were examined using confocal microscopy and Western blotting in the stage of compensated hypertrophy (11 weeks), and decompensated HF (21 weeks). Heart to body weight (BW) ratio was 89% and 133% higher in AVF rats at 11 and 21 weeks, respectively. At 21 weeks but not 11 weeks, AVF rats had pulmonary congestion (increased lung to BW ratio) indicating presence of decompensated HF. The myocytes in left ventricular midmyocardium were significantly thicker (þ8% and þ45%) and longer (þ88% and þ97%). Despite extensive hypertrophy, there was no excessive fibrosis in the AVF ventricles. Distribution and localization of connexin43 were similar between groups, but its phosphorylation was significantly lower in AVF hearts at 21st week, but not 11th week, suggesting that HF,

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“…Pharmacologic inhibition studies suggested that MMP activation is directly implicated in dilative remodeling of the volume-overloaded ventricle (117), but the mechanisms responsible for the distinct cell biological changes and matrix alterations in volume overload remain poorly understood. Bradykinin receptor signaling has been implicated in matrix loss associated with volume overload (118), but the links between specific mechanical stimuli and myocardial cell activation are understudied. The limited data on the matricellular protein profile in volume-overloaded hearts are not accompanied by systematic investigations of the potential role of these proteins.…”

Section: Ecm In Cardiac Pressure and Volume Overloadmentioning

confidence: 99%

The extracellular matrix in myocardial injury, repair, and remodeling

Frangogiannis¹

2017

Journal of Clinical Investigation

392

318

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Left Ventricular Eccentric Remodeling and Matrix Loss Are Mediated by Bradykinin and Precede Cardiomyocyte Elongation in Rats With Volume Overload

Cited by 121 publications

References 23 publications

Mitochondrial DNA Variant for Complex I Reveals a Role in Diabetic Cardiac Remodeling

Mitochondrial DNA Variant for Complex I Reveals a Role in Diabetic Cardiac Remodeling

Myocardial Morphological Characteristics and Proarrhythmic Substrate in the Rat Model of Heart Failure Due to Chronic Volume Overload

The extracellular matrix in myocardial injury, repair, and remodeling

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