Relation between contractile function and regulatory cardiac proteins in hypertrophied hearts

Stein, Birgitt; Bartel, Sabine; Kirchhefer, Uwe; Kokott, Sabine; Krause, Ernst; Neumann, Joachim; Schmitz, Wilhelm; Scholz, Hasso

doi:10.1152/ajpheart.1996.270.6.h2021

Cited by 30 publications

(37 citation statements)

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“…Many β-blocker-associated gene expression changes in responders versus nonresponders represent a partial reversal of the cardiac fetal/adult gene program, 3,34,35 but they may also be consistent with alternative regulatory mechanisms including inhibition of β 1 -AR signaling 5,6,36 or enhanced thyroid hormone receptor (TR-α) activity (Table 5). 7 We previously reported changes in TR-α1 and TR-α2 expression in IDC LVs consistent with hypothyroidism at the TR-α level.…”

Section: Figure 3 Continuedmentioning

confidence: 99%

Therapeutic Molecular Phenotype of β-Blocker–Associated Reverse-Remodeling in Nonischemic Dilated Cardiomyopathy

Kao

Lowes

Gilbert

et al. 2015

Circ Cardiovasc Genet

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volume) to the degree of eccentric hypertrophy (end-diastolic volume [EDV]). IDC in humans is associated with myocardial gene expression changes affecting contractile function and hypertrophy.2,3 Among these are upregulation in mRNA and protein abundances of β-myosin heavy chain (MYH7) and atrial natriuretic peptide (NPPA) with downregulation of α-myosin heavy chain (MYH6) and sarcoplasmic reticulum calcium-ATPase 2 (ATP2A2), a pattern also observed during fetal cardiac development.2,3 Reversal of these pathological changes is associated with ventricular reverse-remodeling in response to both β 1 -selective and nonselective β-adrenergic Background-When β-blockers produce reverse-remodeling in idiopathic dilated cardiomyopathy, they partially reverse changes in fetal-adult/contractile protein, natriuretic peptide, SR-Ca 2+ -ATPase gene program constituents. The objective of the current study was to further test the hypothesis that reverse-remodeling is associated with favorable changes in myocardial gene expression by measuring additional contractile, signaling, and metabolic genes that exhibit a fetal/adult expression predominance, are thyroid hormone-responsive, and are regulated by β 1 -adrenergic receptor signaling. A secondary objective was to identify which of these putative regulatory networks is most closely associated with observed changes. Methods and Results-Forty-seven patients with idiopathic dilated cardiomyopathy (left ventricular ejection fraction, 0.24±0.09) were randomized to the adrenergic-receptor blockers metoprolol (β 1-selective), metoprolol+doxazosin (β 1 /α 1 ), or carvedilol (β 1 /β 2 /α 1 ). Serial radionuclide ventriculography and endomyocardial biopsies were performed at baseline, 3, and 12 months. Expression of 50 mRNA gene products was measured by quantitative polymerase chain reaction. Thirty-one patients achieved left ventricular ejection fraction reverse-remodeling response defined as improvement by ≥0.08 at 12 months or by ≥0.05 at 3 months (Δ left ventricular ejection fraction, 0.21±0.10). Changes in gene expression in responders versus nonresponders were decreases in NPPA and NPPB and increases in MYH6, ATP2A2, PLN, RYR2, ADRA1A, ADRB1, MYL3, PDFKM, PDHX, and CPT1B. All except PDHX involved increase in adult or decrease in fetal cardiac genes, but 100% were concordant with changes predicted by inhibition of β 1 -adrenergic signaling. Conclusions-In addition to known gene expression changes, additional calcium-handling, sarcomeric, adrenergic signaling, and metabolic genes were associated with reverse-remodeling. The pattern suggests a fetal-adult paradigm but may be because of reversal of gene expression controlled by a β 1 -adrenergic receptor gene network. Clinical Trial Registration-URL: www.clinicaltrials.gov. Unique Identifier: NCT01798992.

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Section: Figure 3 Continuedmentioning

confidence: 99%

Therapeutic Molecular Phenotype of β-Blocker–Associated Reverse-Remodeling in Nonischemic Dilated Cardiomyopathy

Kao

Lowes

Gilbert

et al. 2015

Circ Cardiovasc Genet

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“…Because several of these PDEs are also targets of cGMP, it is possible that cGMP may affect cardiac hypertrophy indirectly through modulation of the activity of these PDEs (24), which regulate cAMP levels and, thereby, associated aspects of cardiac contractility. For example, protein kinase A (PKA)-dependent modulation of the L-type calcium channel, cardiac ryanodine receptor, sarcoplasmatic reticulum Ca 2+ -ATPase (SERCA) (25)(26)(27)(28), and calcium has been implicated in cardiac hypertrophy induced by the stimulation of β-adrenergic receptors (β-ARs) (29)(30)(31).…”

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confidence: 99%

Cardiac hypertrophy is not amplified by deletion of cGMP-dependent protein kinase I in cardiomyocytes

Łukowski

Rybalkin

Loga

et al. 2010

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

137

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It has been suggested that cGMP kinase I (cGKI) dampens cardiac hypertrophy. We have compared the effect of isoproterenol (ISO) and transverse aortic constriction (TAC) on hypertrophy in WT [control (CTR)] mice, total cGKI-KO mice, and cGKIβ rescue mice (βRM) lacking cGKI specifically in cardiomyocytes (CMs). Infusion of ISO did not change the expression of cGKI in the hearts of CTR mice or βRM but raised the heart weight by ∼20% in both. An identical hypertrophic growth response was measured in CMs from CTR mice and βRM and in isolated adult CMs cultured with or without 1 μM ISO. In both genotypes, ISO infusion induced similar changes in the expression of hypertrophy-associated cardiac genes and significant elevation of serum atrial natriuretic peptide and total cardiac cGMP. No differences in cardiac hypertrophy were obtained by 7-day ISO infusion in 4-to 6-week-old conventional cGKI-KO and CTR mice. Furthermore, TAC-induced hypertrophy of CTR mice and βRM was not different and did not result in changes of the cGMP-hydrolyzing phosphodiesterase activities in hypertropic hearts or CMs. These results strongly suggest that cardiac myocyte cGKI does not affect the development of heart hypertrophy induced by pressure overload or chronic ISO infusion.cyclic nucleotides | phosphodiesterase | phosphorylation | transverse aortic constriction | sildenafil C linical studies and genetically modified mice have supported the notion that natriuretic peptides (NPs), the particulate guanylyl cyclase (GC)-A, and the second messenger cGMP can attenuate the development of pressure-or volume-induced cardiac hypertrophy and fibrosis (1). Disruption of the murine GC-A gene, the receptor for the cardiac "hormones" atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), results in salt-resistant elevation of blood pressure, cardiac fibrosis, and hypertrophy (2, 3). To a great extent, hypertrophy is independent of blood pressure elevation (4, 5) but is enhanced transverse aortic constriction (TAC) in the absence of GC-A (4). Further studies using cardiac muscle-specific deletion of GC-A confirmed that cardiac muscle hypertrophy is independent of changes in blood pressure (6). ANP, nitric oxide (NO) donors, and 8-Br-cGMP inhibited norepinephrine-induced hypertrophy of cardiac cells and fibroblasts (7,8).Although it is recognized that GC-A-deficient hearts exhibit marked hypertrophy with interstitial fibrosis (2, 9), deletion of ANP did not result in obvious hypertrophy and fibrosis (10). Other reports have indicated that ANP ablation in mice causes an accelerated susceptibility to hypertrophy induced by different stress stimuli (11,12). Obviously, ANP and BNP secreted by the cardiomyocytes (CMs) act as paracrine factors that exert antifibrotic effects in vivo and play a role as local regulators of ventricular remodeling. Furthermore, it has been shown that rats expressing a dominant-negative mutant of GC-B and having an attenuated cGMP response to C-natriuretic peptide and a normal response to ANP showed marked cardiac hyp...

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“…There is considerable controversy about the BP changes due to the ISO-induced cardiac injury. Multiple studies have demonstrated declined pumping ability of the heart (Lin, 1973;Baldwin et al, 1982) and depressed contractile ability of the heart in ISO-induced hypertrophy (Vassallo et al, 1988;Bowling et al, 1990;Stein et al, 1996), while others reported contractile function enhancement (Cihak et al, 1992;Tang and Taylor, 1996;Arthur and Belcastro, 1997). In the present study, rats with hypertrophic hearts exhibited significant elevation in both systolic and diastolic BP, which is in agreement with Papparella et al (2008), who reported increased BP in angiotensin-II-treated rats.…”

Section: Discussionmentioning

confidence: 99%

Down‐regulation of CD68 after simvastatin treatment of isoproterenol‐induced myocardial infarction in rats

Atteya

2016

Int. j. adv. appl. sci.

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Isoproterenol (ISO) induces myocardial injuries in the form of ischemia and infarction (MI). Simvastatin (SIM) is a lipid-soluble inhibitor of hydroxy-3-methylglutaryl coenzyme A reductase with multiple reported therapeutic benefits. The present study was designed to evaluate the effect of pretreatment with SIM on ISO-induced cardiac infarction in rats. Forty-eight rats were divided into four groups. Group I (control) received normal saline. Group II (SIM) received SIM (10 mg/kg body weight, orally by gavage) for 30 days. Group III (ISO) received ISO (5 mg/kg) intraperitoneally for 7 days to induce cardiac injury. Group IV (ISO/SIM); received SIM (10 mg/kg body weight, orally by gavage) for 30 days and in the last 7 days they received ISO (5 mg/kg) intraperitoneally. Serological analysis for detection of cardiac injury markers (troponin-T and creatine phosphokinase-MB "CPK-MB") and inflammatory markers (IL-6 and TNF-α) was done. Cardiac tissues were processed for histological examination (H&E and Masson's trichrome) and for the immunohistological quantitative analysis of CD68. Administration of ISO induced an increase in heart weight to body weight (HW/BW) ratio and elevation of systolic and diastolic blood pressure. Serological analysis revealed an increase of interleukin-6, troponin-T, (CPK-MB), and tumor necrosis factor-α (TNF-α). Histopathological examination of heart tissue revealed thickening of the left ventricle and inter-ventricular septum, large focal areas of sub-endocardial degeneration, mononuclear cellular infiltrations, and massive interstitial fibrosis. In addition, ISO-treated rats exhibited significant up-regulation of CD68. Pre-treatment with SIM significantly attenuated ISO-induced cardiac hypertrophy and necrosis, alleviated the elevated biochemical parameters and CD68 expression, and improved the heart histopathological changes. This study provides evidence that SIM minimizes the ischemic effect of ISO on the heart of rats through inhibition of inflammatory cellular infiltration, especially macrophages, as confirmed by down-regulation of CD68.

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Relation between contractile function and regulatory cardiac proteins in hypertrophied hearts

Cited by 30 publications

References 0 publications

Therapeutic Molecular Phenotype of β-Blocker–Associated Reverse-Remodeling in Nonischemic Dilated Cardiomyopathy

Therapeutic Molecular Phenotype of β-Blocker–Associated Reverse-Remodeling in Nonischemic Dilated Cardiomyopathy

Cardiac hypertrophy is not amplified by deletion of cGMP-dependent protein kinase I in cardiomyocytes

Down‐regulation of CD68 after simvastatin treatment of isoproterenol‐induced myocardial infarction in rats

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