Microarray analysis of gene expression during early stages of mild and severe cardiac hypertrophy

Rajan, Sudarsan; Williams, Sarah S.; Jagatheesan, Ganapathy; Ahmed, Rafeeq; Fuller-Bicer, Geraldine A.; Schwartz, Arnold; Aronow, Bruce J.; Wieczorek, David F.

doi:10.1152/physiolgenomics.00072.2006

Cited by 38 publications

(26 citation statements)

References 30 publications

(40 reference statements)

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“…Thus, these genes demonstrate dominant expression of the PLN KO genotype over the Tm180 hearts by increased expression. This decreased expression of genes associated with metabolic pathways in the hypertrophic Tm180 hearts is in agreement with our previous work (18).…”

Section: Resultssupporting

confidence: 93%

“…All 24 RNA samples used for the microarray experiments were subject to real-time quantitative RT-PCR analysis. Gene-specific real-time RT-PCR primers (Table 1), including those associated with cardiac hypertrophy-associated genes, were used as previously described (18). cDNA was synthesized for 50 min at 50°C in a 20 l reaction containing 1ϫ First-Strand Buffer, 5 g total RNA, 50 ng of random hexamers, 2 M dNTPs, 40 units RNase inhibitor, and 200 units Superscript III RT (Invitrogen).…”

Section: Pln Ko Tm180mentioning

confidence: 99%

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Microarray analysis of active cardiac remodeling genes in a familial hypertrophic cardiomyopathy mouse model rescued by a phospholamban knockout

Rajan

Peña

Jegga

et al. 2013

Physiological Genomics

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Rajan S, Pena JR, Jegga AG, Aronow BJ, Wolska BM, Wieczorek DF. Microarray analysis of active cardiac remodeling genes in a familial hypertrophic cardiomyopathy mouse model rescued by a phospholamban knockout. Physiol Genomics 45: 764 -773, 2013. First published June 25, 2013 doi:10.1152/physiolgenomics.00023.2013.-Familial hypertrophic cardiomyopathy (FHC) is a disease characterized by ventricular hypertrophy, fibrosis, and aberrant systolic and/or diastolic function. Our laboratories have previously developed two mouse models that affect cardiac performance. One mouse model encodes an FHCassociated mutation in ␣-tropomyosin: Glu ¡ Gly at amino acid 180, designated as Tm180. These mice display a phenotype that is characteristic of FHC, including severe cardiac hypertrophy with fibrosis and impaired physiological performance. The other model was a gene knockout of phospholamban (PLN KO), a regulator of calcium uptake in the sarcoplasmic reticulum of cardiomyocytes; these hearts exhibit hypercontractility with no pathological abnormalities. Previous work in our laboratories shows that when mice were genetically crossed between the PLN KO and Tm180, the progeny (PLN KO/Tm180) display a rescued hypertrophic phenotype with improved morphology and cardiac function. To understand the changes in gene expression that occur in these models undergoing cardiac remodeling (Tm180, PLN KO, PLN KO/Tm180, and nontransgenic control mice), we conducted microarray analyses of left ventricular tissue at 4 and 12 mo of age. Expression profiling reveals that 1,187 genes changed expression in direct response to the three genetic models. With these 1,187 genes, 11 clusters emerged showing normalization of transcript expression in the PLN KO/Tm180 hearts. In addition, 62 transcripts are highly involved in suppression of the hypertrophic phenotype. Confirmation of the microarray analysis was conducted by quantitative RT-PCR. These results provide insight into genes that alter expression during cardiac remodeling and are active during modulation of the cardiomyopathic phenotype. tropomyosin; phospholamban; cardiomyopathy; mouse model CARDIOVASCULAR DISEASE IS the leading cause of mortality in the Western world, with heart failure representing one of the fastest growing subgroups over the past decade. Systolic and diastolic dysfunction is common in patients suffering from many types of heart disease and cardiac failure. In addition, hypertrophic growth of cardiomyocytes occurs in many forms of heart failure and may contribute to the pathogenesis of the failure state.Familial hypertrophic cardiomyopathy (FHC) is associated with mutations in contractile proteins of the cardiac sarcomere, Z-disc proteins, and Ca 2ϩ -handling proteins (5). ␣-tropomyosin (Tm), a thin filament protein of the sarcomere, has been found to encode 11 mutations that lead to FHC (23). Previous work in our laboratories established a transgenic mouse model expressing mutant FHC Tm180 protein (1,7,16,17). This mouse develops severe concentric cardiac hypertrophy with si...

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Section: Resultssupporting

confidence: 93%

Section: Pln Ko Tm180mentioning

confidence: 99%

Microarray analysis of active cardiac remodeling genes in a familial hypertrophic cardiomyopathy mouse model rescued by a phospholamban knockout

Rajan

Peña

Jegga

et al. 2013

Physiological Genomics

Self Cite

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“…Elongation of the AMVL was also confirmed. 5 The precise mechanism for this is not known, but sarcomeric protein mutations may influence valvulogenesis through abnormal fibroblastic differentiation of epicardial-derived cells 44 adjacent to the mitral valve which increase levels of periostin, 45 thought to be important in the regulation of valve differentiation and maturation. 46 HCM animal models may aid our understanding of phenotype evolution in preclinical and overt HCM, helping to distinguish between the primary effects of sarcomere mutations and other compensatory structural changes.…”

Section: Discussionmentioning

confidence: 99%

Abnormal Cardiac Formation in Hypertrophic Cardiomyopathy

Captur

Lopes

Patel

et al. 2014

Circ Cardiovasc Genet

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“…In this context, a number of genes altered by HS diet were normalized by PC including the myosin heavy-chain isoform switch characteristic of loaddependent hypertrophy (10,14). Changes in ␣-tropomyosin and in the NF-B pathway, which have been linked with ventricular hypertrophy (31,32), were also positively modified by PC. This is consistent with the finding that 1,25(OH) 2 D 3 significantly blunts the activation of NF-B signaling in vitro (33).…”

Section: Discussionmentioning

confidence: 99%

Activated vitamin D attenuates left ventricular abnormalities induced by dietary sodium in Dahl salt-sensitive animals

Bodyak

Ayus²,

Achinger³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

304

250

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Observations in hemodialysis patients suggest a survival advantage associated with activated vitamin D therapy. Left ventricular (LV) structural and functional abnormalities are strongly linked with hemodialysis mortality. Here, we investigated whether paricalcitol (PC, 19-nor-1,25(OH)2D2), an activated vitamin D compound, attenuates the development of LV abnormalities in the Dahl salt-sensitive (DSS) rat and whether humans demonstrate comparable findings. Compared with DSS rats fed a high-salt (HS) diet (6% NaCl for 6 weeks), HS؉PC was associated with lower heart and lung weights, reduced LV mass, posterior wall thickness and end diastolic pressures, and increased fractional shortening. Blood pressures did not significantly differ between the HS groups. Plasma brain natriuretic peptide levels, and cardiac mRNA expression of brain natriuretic peptide, atrial natriuretic factor, and renin were significantly reduced in the HS؉PC animals. Microarray analyses revealed 45 specific HS genes modified by PC. In a retrospective pilot study of hemodialysis patients, PC-treated subjects demonstrated improved diastolic function and a reduction in LV septal and posterior wall thickness by echocardiography compared with untreated patients. In summary, PC attenuates the development of LV alterations in DSS rats, and these effects should be examined in human clinical trials.cardiac hypertrophy ͉ heart failure ͉ paricalcitol ͉ renal failure T he rate of cardiovascular-related mortality in hemodialysis patients is 10-20 times higher than that observed in the general population (1). Left ventricular hypertrophy (LVH) and diastolic dysfunction are present in Ͼ50% of patients at dialysis initiation, and these abnormalities are strongly linked with dialysis-related mortality (2). Currently, there are no well accepted means to modify cardiac structural and functional alterations in renal-failure patients.We recently demonstrated in observational studies that therapy with activated vitamin D to chronic hemodialysis patients is associated with reduction in cardiovascular-related mortality (3, 4). Conversion of nutritional vitamin D (25(OH)D 3 ) to the hormonally active form of vitamin D (1,25(OH) 2 D 3 ) occurs primarily in the kidney; thus, patients with kidney failure commonly present with altered vitamin D status (5). There is growing evidence that vitamin D either directly or indirectly affects cardiac structure and function. The vitamin D receptor knockout mouse model demonstrates increased cardiac renin expression and marked cardiomyocyte hypertrophy (6), and 1,25(OH) 2 D 3 attenuates cardiomyocyte proliferation (7) and hypertrophy (8) in vitro. Here, we demonstrate that treatment with an activated vitamin D compound attenuates the development of cardiac hypertrophy and dysfunction in a recognized animal model of such abnormalities and that comparable findings are evident in humans.

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Microarray analysis of gene expression during early stages of mild and severe cardiac hypertrophy

Cited by 38 publications

References 30 publications

Microarray analysis of active cardiac remodeling genes in a familial hypertrophic cardiomyopathy mouse model rescued by a phospholamban knockout

Microarray analysis of active cardiac remodeling genes in a familial hypertrophic cardiomyopathy mouse model rescued by a phospholamban knockout

Abnormal Cardiac Formation in Hypertrophic Cardiomyopathy

Activated vitamin D attenuates left ventricular abnormalities induced by dietary sodium in Dahl salt-sensitive animals

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