Adaptive or maladaptive response to adenoviral adrenomedullin gene transfer is context‐dependent in the heart

Leskinen, Hanna; Rauma-Pinola, Tanja; Szokodi, István; Kerkelä, Risto; Pikkarainen, Sampsa; Uusimaa, Paavo; Hautala, Timo; Vuolteenaho, Olli; Ruskoaho, Heikki

doi:10.1002/jgm.1219

Cited by 6 publications

(3 citation statements)

References 44 publications

(56 reference statements)

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“…For example, adrenomedullin gene delivery under identical experimental conditions attenuated angiotensin II-induced LV hypertrophy without compromising cardiac function but enhanced LV dilatation and anterior wall thinning and augmented the deterioration of LV function after infarction. 52 Despite optimal treatment with existing drugs, the prognosis of HF remains poor, and thus therapeutic strategies designed to specifically attenuate myocardial remodeling process would represent a promising new approach to treat patients with HF. Very recently, in a proof-of-concept pilot human study, low-dose intravenous infusion of recombinant BNP for 72 hours preserved ventricular function and structure after MI.…”

Section: Discussionmentioning

confidence: 99%

Intramyocardial BNP Gene Delivery Improves Cardiac Function Through Distinct Context-Dependent Mechanisms

Moilanen

Rysä

Mustonen

et al. 2011

Circ: Heart Failure

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Background-B-type natriuretic peptide (BNP) is an endogenous peptide produced under physiological and pathological conditions mainly by ventricular myocytes. It has natriuretic, diuretic, blood pressure-lowering, and antifibrotic actions that could mediate cardiorenal protection in cardiovascular diseases. In the present study, we used BNP gene transfer to examine functional and structural effects of BNP on left ventricular (LV) remodeling. Methods and Results-Human BNP was overexpressed by using adenovirus-mediated gene delivery in normal rat hearts and in hearts during the remodeling process after infarction and in an experimental model of angiotensin II-mediated hypertension. In healthy hearts, BNP gene delivery into the anterior wall of the LV decreased myocardial fibrosis (PϽ0.01, nϭ7 to 8) and increased capillary density (PϽ0.05, nϭ7 to 8) associated with a 7.3-fold increase in LV BNP peptide levels. Overexpression of BNP improved LV fractional shortening by 22% (PϽ0.05, nϭ6 to 7) and ejection fraction by 19% (PϽ0.05, nϭ6 to 7) after infarction. The favorable effect of BNP gene delivery on cardiac function after infarction was associated with normalization of cardiac sarcoplasmic reticulum Ca 2ϩ -ATPase expression and phospholamban Thr17-phosphorylation. BNP gene delivery also improved fractional shortening and ejection fraction in angiotensin II-mediated hypertension as well as decreased myocardial fibrosis and LV collagen III mRNA levels but had no effect on angiogenesis or Ca 2ϩ -ATPase expression and phospholamban phosphorylation. Conclusions-Local intramyocardial BNP gene delivery improves cardiac function and attenuates adverse postinfarctionand angiotensin II-induced remodeling. These results also indicate that myocardial BNP has pleiotropic, contextdependent, favorable actions on cardiac function and suggest that BNP acts locally as a key mechanical load-activated regulator of angiogenesis and fibrosis. (Circ Heart Fail. 2011;4:483-495.)Key Words: B-type natriuretic peptide Ⅲ gene therapy Ⅲ heart failure Ⅲ myocardial infarction Ⅲ angiogenesis Ⅲ fibrosis H eart failure (HF) is one of the most common causes of cardiovascular morbidity and mortality, and its prevalence is rapidly increasing as the mean age of the population advances. 1 The major cause of systolic HF is coronary artery disease, whereas diastolic HF (HF with preserved ejection fraction [EF]) is more common in patients with hypertension. 2,3 Worsening of chronic systolic or diastolic dysfunction is the most common form of acute HF, accounting for a substantial number of hospitalizations with a poor prognosis. 4 A number of drugs, particularly ␤-blockers and drugs acting on the renin-angiotensin-aldosterone system, have been shown to improve survival in patients who have left ventricular (LV) systolic dysfunction. 2,3 However, identifying appropriate treatments for patients who have HF with preserved EF or acute HF has been a daunting task. [2][3][4] Clinical Perspective on p 495Atrial and B-type natriuretic peptides (ANP and BNP, re...

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Section: Discussionmentioning

confidence: 99%

Intramyocardial BNP Gene Delivery Improves Cardiac Function Through Distinct Context-Dependent Mechanisms

Moilanen

Rysä

Mustonen

et al. 2011

Circ: Heart Failure

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“…The study protocol simulated a protocol used in cardiovascular studies in the University of Oulu. 42–44 However, no surgical procedures were performed. The stress caused by the surgical procedures and the 24 h recovery period in isolation was simulated (to a milder degree) by a 24 h period of isolation in a barren cage.…”

Section: Discussionmentioning

confidence: 99%

The effects of intra-cage aspen tube on cardiac morphology and gene expression

et al. 2010

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According to the European recommendations rodents should be provided with a nest box if there is insufficient nesting material to build a complete, covered nest. Rats are generally poor nest builders; hence an additional structure is needed. Optimally, housing refinement may be combined with better science; at least it should not detract from the scientific integrity. In order to evaluate these options, there is a need to assess the items used in individual research projects. Studies investigating molecular mechanisms of cardiac hypertrophy and heart failure are typically long-lasting studies; therefore, refinement of the housing of rats in these studies is important. The aim of this study was to evaluate in rats whether a wooden tube has any impact on cardiac morphology or on basal gene expression of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP); known markers of cardiac overload, hypertrophy and heart failure. The experimental protocol simulated cardiovascular studies, but without any surgical operations. A total of 42 male Hsd:SD rats were used in an eight-week experiment. After weaning, the experimental group was provided with a rectangular aspen tube and nesting material, and the control group with only nesting material. ANP and BNP gene expression were measured from the left ventricles with Northern blot analysis postmortem along with the absolute weights of the whole heart, left and right atria and left and right chambers. The weights of the whole heart and left chamber were also analysed in relation to body weight. No statistically significant differences were observed in any of these variables. The inter-individual variation was also unchanged by the cage item. In conclusion, the aspen tube does not disrupt research results or alter the number of animals needed and can therefore be recommended for enrichment purposes in cardiovascular studies.

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“…Dimensions of end diastolic interventricular septum (IVSd), diastolic left ventricular posterior wall (LVPWd) and left ventricular ejection fraction (LVEF) were noninvasively measured. Three consecutive cycles of measurements were performed and the results were averaged (16). Echocardiography and the measurement procedure were performed in a double-blind manner.…”

Section: Methodsmentioning

confidence: 99%

Rosuvastatin prevents pressure overload-induced myocardial hypertrophy via inactivation of the Akt, ERK1/2 and GATA4 signaling pathways in rats

Xue

Zhang

Liang

2013

Molecular Medicine Reports

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Pressure overload‑induced myocardial hypertrophy is associated with a poor prognosis in humans and contributes to the development of cardiac arrhythmias, diastolic dysfunction and ultimate congestive heart failure. 3‑Hydroxy‑3‑methylglutaryl‑CoA (HMG‑CoA) reductase inhibitors, also known as statins, have been previously shown to induce regression of myocardial hypertrophy in aortic banding models. However, there is limited knowledge regarding the underlying molecular mechanisms. Therefore, we hypothesized that the myocardial hypertrophy‑related signaling pathways protein kinase B (Akt), extracellular signal‑regulated kinases 1 or 2 (ERK1/2) and GATA binding protein 4 (GATA4) activation pathways constitute targets of rosuvastatin (RSV). Therefore, the above‑mentioned activation pathways were hypothesized to be involved in the regression of pressure overload‑induced myocardial hypertrophy treated by RSV. Twenty‑eight Wistar rats were randomly allocated into 4 groups: the sham operation‑vehicle (SH‑V), abdominal aortic constriction‑vehicle (AAC‑V), abdominal aortic constriction‑RSV 10 mg/kg/day (AAC‑LO) and the abdominal aortic constriction‑RSV 20 mg/kg/day (AAC‑HI) group. Following the establishment of the abdominal aorta constriction model, we investigated the effect of RSV, a new hydrophilic statin, on abdominal aortic constriction‑induced myocardial hypertrophy as well as the underlying intercellular signaling pathways after 5 days and 4 weeks of drug intervention. Moreover, echocardiographic features and the left ventricular weight to final body weight ratio (LVW/BW) were determined. Cross‑sectional areas (CSAs) of cardiomyocytes were assessed by hematoxylin and eosin (H&E) staining. Atrial natriuretic factor (ANF), β‑myosin heavy chain (β‑MHC) and peroxisome proliferator‑activated receptor α (PPARα) messenger RNA (mRNA) expression was assessed using RT‑PCR. The phosphorylation of Akt, ERK1/2 and GATA4 were also examined using western blot analysis. Our results showed that RSV significantly attenuates pressure overload‑induced myocardial hypertrophy by preventing myocardial hypertrophy‑related activation of Akt, ERK1/2 and GATA4 signaling pathways.

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Adaptive or maladaptive response to adenoviral adrenomedullin gene transfer is context‐dependent in the heart

Cited by 6 publications

References 44 publications

Intramyocardial BNP Gene Delivery Improves Cardiac Function Through Distinct Context-Dependent Mechanisms

Intramyocardial BNP Gene Delivery Improves Cardiac Function Through Distinct Context-Dependent Mechanisms

The effects of intra-cage aspen tube on cardiac morphology and gene expression

Rosuvastatin prevents pressure overload-induced myocardial hypertrophy via inactivation of the Akt, ERK1/2 and GATA4 signaling pathways in rats

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