AKAP13 Rho-GEF and PKD-Binding Domain Deficient Mice Develop Normally but Have an Abnormal Response to β-Adrenergic-Induced Cardiac Hypertrophy

Reduced potassium (k+) intake has been linked to cardiovascular diseases. The underlying mechanisms remain unknown. Here, we investigate the effect of low (0%), normal (0.5%) and high K+ (5%) diet on the development of atherosclerosis and hypertensive cardiac damage. To induce atherosclerosis, apolipoprotein-deficient mice were infused with angiotensin (Ang) II (500ng/kg/min) for 28 days. Potassium treatment was initiated 2 weeks before Ang II infusion. Cardiac function was assessed by MRI. Levels of K+ in the serum and urine were significantly different between groups. The Ang II infused mice from the K+ low group had significantly higher atherosclerotic plaques in the aortic arch (21±3%) compared to K+ high (10±2%) and K+ normal (11±2%) groups. The atherosclerosis development was blood pressure independent since no differences in blood pressure between the groups were observed. Although heart to body-weight ratio did not differ between three groups, K+ low diet was associated with a lower ejection fraction rate and increased mRNA expression levels of cardiac ANP, BNP, collagen and fibronectin compared to the K+ normal and K+ high group. After Ang II infusion, assessment of aldosterone levels in urine showed significant higher aldosterone levels in the high K+ (214±72ng/24h) compared to normal K+ (26±6ng/24h) and low K+ (18±4ng/24h) groups. Aldosterone induced cardiovascular damage is known to be aggravated by sodium. To, evaluate whether high sodium diet unmask aldosterone mediated cardiovascular damage in the high K+ group, mice fed a high or normal K+ diet were additionally treated with high sodium (1% NaCl) in the drinking water. During Ang II treatment, high salt diet accelerated atherosclerosis in the aortic arch of both groups but no differences were observed between the high K+ high/high Na+ (41±7%) and normal K+/high Na+ (49±2%) group. In contrast, high K+/high Na+ group have significantly more severe cardiac hypertrophy compared to normal K+ high Na+ group (8.9±0.7 vs 6.4±0.7mg/g). These results were confirmed by MRI. K+ deficient diet induces atherosclerosis and cardiac damage during Ang II induced hypertension. K+ enriched diet exacerbates cardiac hypertrophy only under high Na+ conditions most likely in an aldosterone-dependent mechanism.

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Poly(ADP-ribose) polymerase-1-deficient mice are protected from angiotensin II-induced cardiac hypertrophy

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01124.2005 ◽

2006 ◽

Vol 291 (4) ◽

pp. H1545-H1553 ◽

Cited By ~ 73

Author(s):

Jyothish B. Pillai ◽

Madhu Gupta ◽

Senthilkumar B. Rajamohan ◽

Roberto Lang ◽

Jai Raman ◽

...

Keyword(s):

Oxidative Stress ◽

Cell Death ◽

Angiotensin Ii ◽

Cardiac Hypertrophy ◽

Cell Signaling ◽

Primary Cultures ◽

Heart Weight ◽

Cell Protein ◽

Sequence Of Events ◽

Deficient Mice

Poly(ADP-ribose) polymerase-1 (PARP), a chromatin-bound enzyme, is activated by cell oxidative stress. Because oxidative stress is also considered a main component of angiotensin II-mediated cell signaling, it was postulated that PARP could be a downstream target of angiotensin II-induced signaling leading to cardiac hypertrophy. To determine a role of PARP in angiotensin II-induced hypertrophy, we infused angiotensin II into wild-type (PARP+/+) and PARP-deficient mice. Angiotensin II infusion significantly increased heart weight-to-tibia length ratio, myocyte cross-sectional area, and interstitial fibrosis in PARP+/+ but not in PARP−/− mice. To confirm these results, we analyzed the effect of angiotensin II in primary cultures of cardiomyocytes. When compared with PARP−/− cardiomyocytes, angiotensin II (1 μM) treatment significantly increased protein synthesis in PARP+/+ myocytes, as measured by 3H-leucine incorporation into total cell protein. Angiotensin II-mediated hypertrophy of myocytes was accompanied with increased poly-ADP-ribosylation of nuclear proteins and depletion of cellular NAD content. When cells were treated with cell death-inducing doses of angiotensin II (10–20 μM), robust myocyte cell death was observed in PARP+/+ but not in PARP−/− myocytes. This type of cell death was blocked by repletion of cellular NAD levels as well as by activation of the longevity factor Sir2α deacetylase, indicating that PARP induction and subsequent depletion of NAD levels are the sequence of events causing angiotensin II-mediated cardiomyocyte cell death. In conclusion, these results demonstrate that PARP is a nuclear integrator of angiotensin II-mediated cell signaling contributing to cardiac hypertrophy and suggest that this could be a novel therapeutic target for the management of heart failure.

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Cardiac hypertrophy and decreased high-density lipoprotein cholesterol in Lrig3-deficient mice

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00309.2015 ◽

2016 ◽

Vol 310 (11) ◽

pp. R1045-R1052 ◽

Cited By ~ 8

Author(s):

Martin Hellström ◽

Madelene Ericsson ◽

Bengt Johansson ◽

Mahmood Faraz ◽

Fredrick Anderson ◽

...

Keyword(s):

Blood Pressure ◽

Cardiac Hypertrophy ◽

High Density Lipoprotein ◽

Heart Function ◽

Plasma Lipid ◽

Density Lipoprotein ◽

Hdl Cholesterol ◽

Wild Type ◽

Lipid Levels ◽

Deficient Mice

Genetic factors confer risk for cardiovascular disease. Recently, large genome-wide population studies have shown associations between genomic loci close to LRIG3 and heart failure and plasma high-density lipoprotein (HDL) cholesterol level. Here, we ablated Lrig3 in mice and investigated the importance of Lrig3 for heart function and plasma lipid levels. Quantitative reverse transcription-polymerase chain reaction (RT-PCR) was used to analyze Lrig3 expression in the hearts of wild-type and Lrig3-deficient mice. In addition, molecular, physiological, and functional parameters such as organ weights, heart rate, blood pressure, heart structure and function, gene expression in the heart, and plasma insulin, glucose, and lipid levels were evaluated. The Lrig3-deficient mice were smaller than the wild-type mice but otherwise appeared grossly normal. Lrig3 was expressed at detectable but relatively low levels in adult mouse hearts. At 9 mo of age, ad libitum-fed Lrig3-deficient mice had lower insulin levels than wild-type mice. At 12 mo of age, Lrig3-deficient mice exhibited increased blood pressure, and the Lrig3-deficient female mice displayed signs of cardiac hypertrophy as assessed by echocardiography, heart-to-body weight ratio, and expression of the cardiac hypertrophy marker gene Nppa. Additionally, Lrig3-deficient mice had reduced plasma HDL cholesterol and free glycerol. These findings in mice complement the human epidemiological results and suggest that Lrig3 may influence heart function and plasma lipid levels in mice and humans.

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Cardiac Hypertrophy Is Associated With Decreased eNOS Expression in Angiotensin AT 2 Receptor–Deficient Mice

Hypertension ◽

10.1161/01.hyp.0000100445.80029.8e ◽

2003 ◽

Vol 42 (6) ◽

pp. 1177-1182 ◽

Cited By ~ 62

Author(s):

Marc Brede ◽

Wilhelm Roell ◽

Oliver Ritter ◽

Frank Wiesmann ◽

Roland Jahns ◽

...

Keyword(s):

Cardiac Hypertrophy ◽

Enos Expression ◽

Deficient Mice

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Cyclophilin A Promotes Cardiac Hypertrophy in Apolipoprotein E–Deficient Mice

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.110.214601 ◽

2011 ◽

Vol 31 (5) ◽

pp. 1116-1123 ◽

Cited By ~ 52

Author(s):

Kimio Satoh ◽

Patrizia Nigro ◽

Asad Zeidan ◽

Nwe Nwe Soe ◽

Fabrice Jaffré ◽

...

Keyword(s):

Cardiac Hypertrophy ◽

Apolipoprotein E ◽

Cyclophilin A ◽

Deficient Mice

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Myoglobin-deficient mice activate a distinct cardiac gene expression program in response to isoproterenol-induced hypertrophy

Physiological Genomics ◽

10.1152/physiolgenomics.90297.2008 ◽

2010 ◽

Vol 41 (2) ◽

pp. 137-145 ◽

Cited By ~ 23

Author(s):

Andrei Molojavyi ◽

Antje Lindecke ◽

Annika Raupach ◽

Sarah Moellendorf ◽

Karl Köhrer ◽

...

Keyword(s):

Gene Expression ◽

Cardiac Hypertrophy ◽

Left Ventricular ◽

Gene Expression Program ◽

Cardiac Stress ◽

Cardiac Gene Expression ◽

Left Ventricular Dilatation ◽

Cardiac Gene ◽

Expression Program ◽

Deficient Mice

Myoglobin knockout mice (myo−/−) adapt to the loss of myoglobin by the activation of a variety of compensatory mechanisms acting on the structural and functional level. To analyze to what extent myo−/− mice would tolerate cardiac stress we used the model of chronic isoproterenol application to induce cardiac hypertrophy in myo−/− mice and wild-type (WT) controls. After 14 days of isoproterenol infusion cardiac hypertrophy in WT and myo−/− mice reached a similar level. WT mice developed lung edema and left ventricular dilatation suggesting the development of heart failure. In contrast, myo−/− mice displayed conserved cardiac function and no signs of left ventricular dilatation. Analysis of the cardiac gene expression profiles using 40K mouse oligonucleotide arrays showed that isoproterenol affected the expression of 180 genes in WT but only 92 genes of myo−/− hearts. Only 40 of these genes were regulated in WT as well as in myo−/− hearts. In WT hearts a pronounced induction of genes of the extracellular matrix occurred suggesting a higher level of cardiac remodeling. myo−/− hearts showed altered transcription of genes involved in carbon metabolism, inhibition of apoptosis and muscular repair. Interestingly, a subset of genes that was altered in myo−/− mice already under basal conditions was differentially expressed in WT hearts under isoproterenol treatment. In summary, our data show a high capacity of myoglobin-deficient mice to adapt to catecholamine induced cardiac stress which is associated with activation of a distinct cardiac gene expression program.

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Guanylyl Cyclase-A Inhibits Angiotensin II Type 2 Receptor-Mediated Pro-Hypertrophic Signaling in the Heart

Endocrinology ◽

10.1210/en.2008-1353 ◽

2009 ◽

Vol 150 (8) ◽

pp. 3759-3765 ◽

Cited By ~ 11

Author(s):

Yuhao Li ◽

Yoshihiko Saito ◽

Koichiro Kuwahara ◽

Xianglu Rong ◽

Ichiro Kishimoto ◽

...

Keyword(s):

Angiotensin Ii ◽

Cardiac Hypertrophy ◽

Guanylyl Cyclase ◽

Weight Ratio ◽

Cross Sectional ◽

Cardiac Phenotype ◽

At1 Antagonist ◽

Hypertrophic Signaling ◽

Deficient Mice

Angiotensin II plays a key role in the development of cardiac hypertrophy. The contribution of the angiotensin II type 1 receptor (AT1) in angiotensin II-induced cardiac hypertrophy is well established, but the role of AT2 signaling remains controversial. Previously, we have shown that natriuretic peptide receptor/guanylyl cyclase-A (GCA) signaling protects the heart from hypertrophy at least in part by inhibiting AT1-mediated pro-hypertrophic signaling. Here, we investigated the role of AT2 in cardiac hypertrophy observed in mice lacking GCA. Real-time RT-PCR and immunoblotting approaches indicated that the cardiac AT2 gene was overexpressed in GCA-deficient mice. Mice lacking AT2 alone did not exhibit an abnormal cardiac phenotype. In contrast, GCA-deficiency-induced increases in heart to body weight ratio, cardiomyocyte cross-sectional area, and collagen accumulation as evidenced by van Gieson staining were attenuated when AT2 was absent. Furthermore, the up-regulated cardiac expression of hypertrophy-related genes in GCA-null animals was also suppressed. Pharmacological blockade of AT2 with PD123319 similarly attenuated cardiac hypertrophy in GCA-deficient mice. In addition, whereas the AT1 antagonist olmesartan attenuated cardiac hypertrophy in GCA-deficient mice, this treatment was without effect on cardiac hypertrophy in GCA/AT2-double null mice, notwithstanding its potent antihypertensive effect in these animals. These results suggest that the interplay of AT2 and AT1 may be important in the development of cardiac hypertrophy. Collectively, our findings support the assertion that GCA inhibits AT2-mediated pro-hypertrophic signaling in heart and offer new insights into endogenous cardioprotective mechanisms during disease pathogenesis.

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