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Secondhand smoke exposure toxicity accelerates age-related cardiac disease in old hamsters
https://doi.org/10.1186/1471-2261-14-195
© Wu et al.; licensee BioMed Central. 2014
Received: 8 September 2014
Accepted: 11 December 2014
Published: 19 December 2014
Abstract
Background
Aging is associated with physiological or pathological left ventricular hypertrophy (LVH) cardiac changes. Secondhand smoke (SHS) exposure is associated with pathological LVH. The action mechanism in cardiac concentric hypertrophy from SHS exposure is understood, but the transition contributed from SHS exposure is not. To determine whether exposure to SHS has an impact on age-induced LVH we examined young and old hamsters that underwent SHS exposure in a chamber for 30 mins.
Methods
Morphological and histological studies were then conducted using hematoxylin and eosin (H&E) and Masson’s trichrome staining. Echocardiographic analysis was used to determine left ventricular wall thickness and function. LVH related protein expression levels were detected by western blot analysis.
Results
The results showed that both young and aged hamsters exposed to SHS exhibited increased heart weights and left ventricular weights, left ventricular posterior wall thickness and intraventricular septum systolic and diastolic pressure also increased. However, left ventricular function systolic and diastolic pressure deteriorated. H&E and Masson’s trichrome staining results showed LV papillary muscles were ruptured, resulting in lower cardiac function at the myocardial level. LV muscle fiber arrangement was disordered and collagen accumulation occurred. Concentric LVH related protein molecular markers increased only in young hamsters exposed to SHS. However, this declined with hamster age. By contrast, eccentric LVH related proteins increased in aging hamsters exposed the SHS. Pro-inflammatory proteins, IL-6, TNF-α, JAK1, STAT3, and SIRTI expression increased in aging hamsters exposed to SHS.
Conclusions
We suggest that SHS exposure induces a pro-inflammatory response that results in concentric transition to aging eccentric LVH.
Keywords
Background
Secondhand smoke (SHS) exposure is a well known contributor to cardiovascular disease among non-smokers [1, 2]. Little known about how SHS exposure affects aging changes. The molecular mechanisms of cardiac aging exposed to SHS are still unclear, especially, the transition from concentric to eccentric left ventricular hypertrophy. This study attempts to determine whether SHS exposure leads the transition from concentric to eccentric left ventricular hypertrophy (LVH) using molecular signaling pathway regulation markers. SHS genotoxicity leading to cardiovascular diseases resulting in human pathological cardiac hypertrophy has been confirmed [3, 4]. Previous studies elucidated that cigarette SHS exposure among children [5, 6] might cause irreversible impairment in endothelium-dependent vasodilation, but the impact in old age is still unclear. The aging heart undergoes slowly progressive structural changes and functional decline with age [7, 8]. A number of pathological mechanisms may arise from the deleterious effects of SHS exposure [6]. The physiologic changes in the aging cardiac include left ventricular hypertrophy, increased cardiac fibrosis and valvular degeneration [9, 10]. Aging changes in the elderly heart are associated with physiological and pathological LV hypertrophy. Aging heart changes can produce cardiac diseases, including coronary arteries [11], myocardial infarction, cardiac valves, aortic regurgitation [12, 13]. Without a doubt, LV hypertrophy is related to changes in cardiac morphology including increased myocyte size [14], increased left ventricular wall thickness and decreased fiber density [15, 16]. Once the aging heart experiences extended elevated workload, the left ventricle becomes deficient in pumping adequate blood. Thus, pathological aging related LV hypertrophy [17] may be associated with cardiovascular disease [18]. The physiological aging associated changes [19] in the heart cannot be reversed and deteriorate in function. The transition between LV concentric hypertrophy and LV eccentric hypertrophy is our interest.
Methods
Animals
We purchased male hamsters at ages 6 weeks and 72 weeks from the National Science Council Animal Center. The animals were group-housed six per cage in an animal room. The experimental protocols were conducted in accordance with committee approved animal care and experimental guidelines from the Taiwan Society for Laboratory Animals Sciences. Male hamsters were used in these studies. Only male hamsters are used to reduce the potential for variability from gender-related differences in cardiac aging. All the animal handling protocols were reviewed and approved by the Institutional Review Board (IRB), Animal care and use committee of the China Medical University, Taichung, Taiwan (ROC).
Experimental design and secondhand smoke (SHS) exposures
Young and aged groups were divided into two subgroups for secondhand smoke (SHS) exposure. (1) control; hamsters were not exposed to secondhand cigarette smoke. (2) SHS exposure; hamsters exposed to cigarette secondhand smoke. The four groups of hamsters were subjected to experiments as follows: MYC; male young control, MYS; male young SHS exposure, MOC; male old control, MOS; male old SHS exposure. Hamsters were placed in an exposure chamber and then exposed to 10 cigarettes for 30 min, 4 weeks [19].
Hematoxylin-eosin and Masson’s trichrome staining
To assess the left ventricle cross-sectional area and extracellular space, the cross sections were stained with hematoxylin and eosin and incubated for 5 min. Part of the left ventricular cross section was stained with Masson’s trichrome to detect collagen accumulation. The stained sections were then rinsed with PBS and air dried before mounting. After gently rinsing with water, the slides were dehydrated through a graded alcohol series for 15 min, cleaned in xylene and then covered with a slip.
Left ventricular tissue collection and extraction
After the animal was sacrificed, the atrium and right ventricle were removed. The left ventricle was rinsed in normal saline and then weighed for left ventricular mass. Left ventricular tissue extracts were obtained at a concentration of 0.1 g tissue/mL PBS by homogenizing. The homogenates were then placed and centrifuged at 12,000 rpm for 30 mins.
Immunohistochemistry analysis
The left ventricular samples from young and old hamsters were fixed and embedded in paraffin. Ten micrometer thick tissue sections were cut and then dewaxed and rehydrated. Slides were blocked in 0.1% bovine serum albumin with PBS buffer for 30 mins at room temperature and incubated with mouse SIRT1 monoclonal antibody in PBS for 2 hrs. After washing, sections were incubated for 30 mins with secondary antibody. After 5 mins washing, peroxidase was developed using diaminobenzidine chromogen (DAB) diluted in H2O2 buffer.
Echocardiography
Hamsters were anesthetized with an intraperitoneal ketamine-xylazine-atropine mixture. We used a commercially available echocardiography system equipped with a 14 MHz liner transducer. Transthoracic echocardiography was performed on young control, old control and 2 or 4 weeks SHS exposure treated in young and old hamsters, using a HDI-5000 ultrasound machine [20]. The following parameters were measured and calculated using the M-mode image: left ventricular posterior at diastolic (LVPWd) and systolic (LVPWs) wall thickness, intraventricular septal at diastolic (IVSd) and systolic (IVSs), fractional shortening (FS%) and ejection fractional (EF%). All data were transferred online to computer for subsequent analysis.
Western blotting analysis
Left ventricular samples (1 ug) were homogenized for 5 min and centrifuged at 8,000 g for 20 min. Proteins were electrophoresed by 10% polyacrylamide gels at 110 V for 90 min, and then transferred to PVDF paper at 100 mA for 2.5 hr. Incubated PVDF members in 1% BSA blocking buffer for 1 hr at room temperature. Polyclonal antibodies, ANP, BNP, p-MEK1, MEK1, p-ERK1/2, ERK1/2, GATA4, IL-6, TNF α, JAK1, STAT3, Calcineurin, p-NFAT, NFAT, p-MEK5, MEK5, p-ERK5 and ERK5 were incubated at room temperature for 2 hr. The immunoblots were washed three times in 5 ml and then incubated in the second antibody solution containing anti-rabbit, or anti-goat, or anti-mouse IgG horseradish peroxidase for 1 hr. Color development was presented in ECL.
Statistical analysis
All data were assessed as the mean ± SD. The experimental results two-way ANOVA analysis was used to assess male young control (MYC), male young SHS exposure (MYS), male old control (MOC), and male old SHS exposure (MOS) groups. *p < 0.05, **p < 0.01, significant difference compared with male young control (MYC). #p < 0.05, ##p < 0.01, significant difference compared with male old control (MOC).
Results
Heart and left ventricular characteristics
Morphology of the left ventricle in male young control (MYC), male young SHS exposure (MYS), male old control (MOC) and male old SHS exposure (MOS) hamsters
Young | Old | |||
---|---|---|---|---|
MYC | MYS | MOC | MOS | |
Animal number (N) | 6 | 6 | 6 | 6 |
BW (g) | 132.54 ± 4.61 | 145.67 ± 3.42* | 130.26 ± 6.04 | 127.59 ± 3.52*♦# |
HW (g) | 0.46 ± 0.01 | 0.52 ± 0.01* | 0.60 ± 0.03**♦ | 0.63 ± 0.03**♦♦# |
LV (g) | 0.31 ± 0.01 | 0.39 ± 0.01 | 0.42 ± 0.01**♦ | 0.53 ± 0.01**♦♦# |
HW/BW (mg/g) | 3.59 ± 0.10 | 3.88 ± 0.07 | 4.45 ± 0.15**♦ | 5.85 ± 0.38**♦♦# |
LV/BW (mg/g) | 2.44 ± 0.05 | 2.67 ± 0.11 | 3.27 ± 0.05**♦ | 4.01 ± 0.20**♦♦# |
HW/tibia (mg/mm) | 16.21 ± 0.23 | 19.14 ± 0.36 | 19.84 ± 0.36**♦ | 24.30 ± 0.70**♦♦# |
LV/tibia (mg/mm) | 11.12 ± 0.25 | 13.66 ± 0.47 | 14.73 ± 0.20**♦ | 18.48 ± 0.48**♦♦# |
The SHS exposure effect on cardiac function in young and old hamsters
Changes characteristic of left ventricle in male young control (MYC), male young SHS exposure (MYS), male old control (MOC) and male old SHS exposure (MOS) hamsters
Unit | MYC | MYS | MOC | MOS | ||
---|---|---|---|---|---|---|
Animals | 6 | 6 | 6 | 6 | ||
LVPWd | (baseline) | mm | 0.9 ± 0.2 | 0.9 ± 0.2 | 1.0 ± 0.1 | 1.0 ± 0.4 |
LVPWd | (2 weeks) | mm | 1.2 ± 0.1 | 1.9 ± 0.1* | 1.9 ± 0.1* | 2.0 ± 0.3*# |
LVPWd | (4 weeks) | mm | 1.5 ± 0.2 | 2.0 ± 0.7* | 2.0 ± 0.1* | 2.0 ± 0.2* |
LVPWs | (baseline) | mm | 1.7 ± 0.1 | 1.7 ± 0.7 | 1.7 ± 0.1 | 1.9 ± 0.3* |
LVPWs | (2 weeks) | mm | 1.7 ± 0.1 | 1.7 ± 0.3 | 2.0 ± 0.2* | 2.0 ± 0.2* |
LVPWs | (4 weeks) | mm | 1.7 ± 0.1 | 2.0 ± 0.1* | 2.0 ± 0.1* | 2.0 ± 0.3* |
IVSd | (baseline) | mm | 1.0 ± 0.1 | 1.0 ± 0.1 | 1.0 ± 0.1 | 1.1 ± 0.1 |
IVSd | (2 weeks) | mm | 1.3 ± 0.1 | 1.3 ± 0.1 | 1.3 ± 0.1 | 1.5 ± 0.3*# |
IVSd | (4 weeks) | mm | 1.5 ± 0.1 | 2.0 ± 0.3* | 2.0 ± 0.2* | 2.0 ± 0.3* |
IVSs | (baseline) | mm | 1.3 ± 0.1 | 1.4 ± 0.2 | 1.7 ± 0.3* | 1.6 ± 0.2* |
IVSs | (2 weeks) | mm | 1.5 ± 0.2 | 1.9 ± 0.1* | 1.9 ± 0.1* | 2.0 ± 0.1*# |
IVSs | (4 weeks) | mm | 1.6 ± 0.2 | 2.1 ± 0.2* | 2.0 ± 0.1* | 2.1 ± 0.1* |
Left ventricular function
Young | Old | ||||
---|---|---|---|---|---|
Unit | MYC | MYS | MOC | MOS | |
EF (baseline) | % | 82.05 ± 5.48 | 72.91 ± 3.47 | 67.88 ± 8.03* | 66.47 ± 6.26* |
EF (2 weeks) | % | 83.63 ± 1.20 | 67.33 ± 7.75* | 62.12 ± 2.82* | 58.33 ± 2.67**# |
EF (4 weeks) | % | 79.33 ± 1.84 | 66.33 ± 3.18* | 62.30 ± 2.66* | 40.14 ± 8.57**# |
FS (baseline) | % | 45.99 ± 5.46 | 40.51 ± 2.85 | 33.15 ± 5.50* | 31.49 ± 4.71* |
FS (2 weeks) | % | 45.28 ± 2.28 | 32.33 ± 5.24* | 31.90 ± 1.64* | 27.33 ± 1.67**# |
FS (4 weeks) | % | 41.28 ± 2.48 | 32.05 ± 2.52* | 27.75 ± 2.27* | 17.67 ± 4.67**# |
Changes in left ventricular architecture in male young control, male young SHS exposure, male old control and male old SHS exposure hamsters
Representative histological cross sections of the left ventricle (LV) stained with hematoxylin-eosin stain and Masson’s trichrome staining. Substantial left ventricles remodeling in old age heart and secondhand smoke exposure. (A) Morphological features of the left ventricle of hematoxylin-eosin stained. Morphometric samples are at x100 magnification (up-panel). Morphometric samples are at x400 magnification) (down-panel). The arrow points to the papillary muscle. (B) Histological examination of LV fibrosis by Masson’s trichrome staining. Morphological features of left ventricular hematoxylin-eosin stained. Morphometric samples are at x100 magnification (up-panel). Morphometric samples are at x400 magnification) (down-panel). The long arrow points to the papillary muscle, short arrow points to collagen. (C) western blotting for ANP and BNP protein in MYC, MYS, MOC and MOS groups from the indicated left ventricular extracts. (D). Statistical analysis ANP and BNP protein expression levels in MYC, MYS, MOC and MOS groups. Data are means ± SD. *P < 0.05, **P < 0.01 significantly statistical differences vs. MYC group (two-way ANOVA). MYC; male young control, MYS; male young SHS exposure, MOC; male old control, MOS; male old SHS exposure.
Molecular characterization of MEK1-ERK1/2-GATA4 signaling pathway in regulation of concentric left ventricular hypertrophy
MEK1-ERK1/2-GATA4 signaling pathway in male young exposure to SHS promotes left ventricular concentric hypertrophy. (A). Western blot analysis of p-MEK1, MEK 1, p-ERK1/2, ERK1/2 and GATA4 protein expression in the MYC, MYS, MOC and MOS groups. (B). Quantification of densitometry analysis of protein expression levels. Statistical analysis of the p-MEK1/MEK1 and p-ERK1/2/ERK1/2 ratios and GATA4 densitometry in MYC, MYS, MOC and MOS groups. All data are presented as means ± SD. *p < 0.05, **p < 0.01 significantly statistical differences compared with male young control (MYC). *p < 0.05, **p < 0.01 significantly statistical differences compared with male old control (MOC).
Inflammatory response evidences linking secondhand smoke (SHS) exposure with pathological age-related diseases
Inflammatory cytokines, IL-6, TNFα, JAK1 and STAT3 mediated eccentric left ventricular hypertrophy in aging and aged SHS exposure hamsters. (A). Western blot analysis of Inflammatory protein, IL-6 and TNFα, expression in MYC, MYS, MOC and MOS groups. (B). Quantification of densitometry analysis of IL-6 and TNFα protein expression levels. Statistical analysis of IL-6 and TNFα protein expression levels in MYC, MYS, MOC and MOS groups. All data are presented as means ± SD. *p < 0.05, **p < 0.01 significant statistical differences compared with male young control (MYC). (C). Western blot and immunohistochemical analysis detection of SIRT1 in the four experimental groups were measured. (D). Western blot analysis of cytokines, JAK1 and STAT3 protein expression in MYC, MYS, MOC and MOS groups. (E). Quantification of densitometry analysis of JAK1 and STAT3 protein expression levels. All data are presented as means ± SD. *p < 0.05, **p < 0.01 significant statistical differences compared with male young control (MYC).
Calcineurin/NFAT-MEK5-ERK5 signaling pathway induced aging related pathological left ventricular eccentric hypertrophy
Stimulation of calcineurin-NFAT, p-MEK5-MEK5, and p-ERK5-ERK5 activation promote eccentric left ventricular hypertrophy in aging and aged SHS exposure. (A). Protein expression levels of calcineurin, NFAT, p-NFAT, p-MEK5, MEK5, p-ERK5 and ERK5 in the MYC, MYS, MOC and MOS groups were measured by western blotting analysis. (B). Statistical analysis of calcineurin densitometry and NFAT/p-NFAT, p-MEK5/MEK5, and p-ERK5/ERK5 ratios in MYC, MYS, MOC and MOS groups. All data are presented as means ± SD. *p < 0.05, **p < 0.01 significant statistical differences compared with male young control (MYC).
Conclusions
The underlying of pathophysiological mechanisms related to aging exposure to SHS are depicted. Inflamm-aging changes lead to concentric LV hypertrophy transfer to eccentric LV hypertrophy.
Declarations
Acknowledgement
This work was supported by a grant from the National Science Council, Republic of China (NSC 100-2314-B-039-018) and Taiwan Ministry of Health and Welfare Clinical Trial and Research Center of Excellence (MOHW103-TDU-B-212-113002). The authors declare that there are no conflicts of interest.
Authors’ Affiliations
References
- Hoegg UR: Cigarette smoke in closed spaces. Environ Health Perspect. 1972, 2: 117-128.View ArticlePubMedPubMed CentralGoogle Scholar
- Tong EK, Glantz SA: Tobacco industry efforts undermining evidence linking secondhand smoke with cardiovascular disease. Circulation. 2007, 116: 1845-1854. 10.1161/CIRCULATIONAHA.107.715888.View ArticlePubMedGoogle Scholar
- Bard RL, Dvonch JT, Kaciroti N, Lustig SA, Brook RD: Is acute high-dose secondhand smoke exposure always harmful to microvascular function in healthy adults?. Prev Cardiol. 2010, 13: 175-179. 10.1111/j.1751-7141.2010.00074.x.View ArticlePubMedGoogle Scholar
- Weeks SG, Glantz SA, De Marco T, Rosen AB, Fleischmann KE: Secondhand smoke exposure and quality of life in patients with heart failure. Arch Intern Med. 2011, 171: 1887-1893. 10.1001/archinternmed.2011.518.View ArticlePubMedGoogle Scholar
- Slayton RL: Exposure to secondhand smoke may cause dental caries in children. J Evid Based Dent Pract. 2012, 12: 8-9. 10.1016/j.jebdp.2011.12.004.View ArticlePubMedGoogle Scholar
- Heiss C, Amabile N, Lee AC, Real WM, Schick SF, Lao D: Brief secondhand smoke exposure depresses endothelial progenitor cells activity and endothelial function: sustained vascular injury and blunted nitric oxide production. J Am Coll Cardiol. 2008, 51: 1760-1771. 10.1016/j.jacc.2008.01.040.View ArticlePubMedGoogle Scholar
- Dai DF, Chen T, Johnson SC, Szeto H, Rabinovitch PS: Cardiac aging: from molecular mechanisms to significance in human health and disease. Antioxid Redox Signal. 2012, 16: 1492-1526. 10.1089/ars.2011.4179.View ArticlePubMedPubMed CentralGoogle Scholar
- Whittington HJ, Harding I, Stephenson CI, Bell R, Hausenloy DJ, Mocanu MM, Yellon DM: Cardio protection in the aging, diabetic heart: the loss of protective Akt signaling. Cardiovasc Res. 2013, 99: 694-704. 10.1093/cvr/cvt140.View ArticlePubMedPubMed CentralGoogle Scholar
- Waller BF: The old-age heart: normal aging changes which can produce or mimic cardiac disease. Clin Cardiol. 1988, 11: 513-517. 10.1002/clc.4960110802.View ArticlePubMedGoogle Scholar
- Sugiura M: Characteristic features of the heart disease in the elderly. Nihon Ronen Igakkai Zasshi. 1994, 31: 182-186.View ArticlePubMedGoogle Scholar
- Hacker TA, McKiernan SH, Douglas PS, Wanagat J, Aiken JM: Age-related changes in cardiac structure and function in Fischer 344 x Brown Norway hybrid rats. Am J Physiol Heart Circ Physiol. 2006, 290: H304-H311.View ArticlePubMedGoogle Scholar
- Nadal-Ginard B, Kajstura J, Leri A, Anversa P: Myocyte death, growth, and regeneration in cardiac hypertrophy and failure. Circ Res. 2003, 92: 139-150. 10.1161/01.RES.0000053618.86362.DF.View ArticlePubMedGoogle Scholar
- Juonala M, Magnussen CG, Venn A, Gall S, Kähönen M, Laitinen T: Parental smoking in childhood and brachial artery flow-mediated dilatation in young adults: the cardiovascular risk in young Finns study and the childhood determinants of adult health study. Arterioscler Thromb Vasc Biol. 2012, 32: 1024-1031. 10.1161/ATVBAHA.111.243261.View ArticlePubMedGoogle Scholar
- Martin Rdos S, Martin LC, Franco RJ, Barretti P, Caramori JC, Castro JH: Ventricular hypertrophy and cardiovascular mortality in hemodialysis patients with low educational level. Arq Bras Cardiol. 2012, 98: 52-61. 10.1590/S0066-782X2012005000004.View ArticlePubMedGoogle Scholar
- van Eps CL, Jeffriess L, Haluska B, Hawley CM, Coombes J: Cardiac and vascular structure and function parameters do not improve with alternate nightly home hemodialysis: an interventional cohort study. BMC Nephrol. 2011, 12: 51-10.1186/1471-2369-12-51.View ArticlePubMedPubMed CentralGoogle Scholar
- Olivetti G, Melissari M, Capasso JM, Anversa P: Cardiomyopathy of the aging human heart. Myocyte loss and reactive cellular hypertrophy. Circ Res. 1991, 68: 1560-1568. 10.1161/01.RES.68.6.1560.View ArticlePubMedGoogle Scholar
- Roffe C: Ageing of the heart. Br J Biomed Sci. 1998, 55: 136-148.PubMedGoogle Scholar
- Anversa P, Palackal T, Sonnenblick EH, Olivetti G, Meggs LG, Capasso JM: Myocyte cell loss and myocyte cellular hyperplasia in the hypertrophied aging rat heart. Circ Res. 1990, 67: 871-885. 10.1161/01.RES.67.4.871.View ArticlePubMedGoogle Scholar
- Kuo WW, Wu CH, Lee SD, Lin JA, Chu CY, Hwang JM: Second-hand smoke-induced cardiac fibrosis is related to the Fas death receptor apoptotic pathway without mitochondria-dependent pathway involvement in rats. Environ Health Perspect. 2005, 113: 1349-1353. 10.1289/ehp.7479.View ArticlePubMedPubMed CentralGoogle Scholar
- Cittadini A, Grossman JD, Strömer H, Katz SE: Importance of an intact growth hormone/insulin-like growth factor 1 axis for normal post-infarction healing: studies in dwarf rats. Endocrinology. 2001, 142: 332-338.PubMedGoogle Scholar
- Helms SA, Azhar G, Zuo C, Theus SA, Bartke A, Wei JY: Smaller cardiac cell size and reduced extra-cellular collagen might be beneficial for hearts of Ames dwarf mice. Int J Biol Sci. 2010, 6: 475-490.View ArticlePubMedPubMed CentralGoogle Scholar
- Arai S, Machida A: Myocardial cell in left ventricular hypertrophy. Tohoku J Exp Med. 1972, 108: 361-367. 10.1620/tjem.108.361.View ArticlePubMedGoogle Scholar
- Raya TE, Gaballa M, Anderson P, Goldman S: Left ventricular function and remodeling after myocardial infarction in aging rats. Am J Physiol. 1997, 273: H2652-H2658.PubMedGoogle Scholar
- North BJ, Sinclair DA: The intersection between aging and cardiovascular disease. Circ Res. 2012, 110: 1097-1108. 10.1161/CIRCRESAHA.111.246876.View ArticlePubMedPubMed CentralGoogle Scholar
- Schick SF, Glantz SA: Side stream cigarette smoke toxicity increases with aging and exposure duration. Tob Control. 2006, 15: 424-429. 10.1136/tc.2006.016162.View ArticlePubMedPubMed CentralGoogle Scholar
- Priebe HJ: The aged cardiovascular risk patient. Br J Anaesth. 2000, 85: 763-778. 10.1093/bja/85.5.763.View ArticlePubMedGoogle Scholar
- Barry SP, Davidson SM, Townsend PA: Molecular regulation of cardiac hypertrophy. Int J Biochem Cell Biol. 2008, 40: 2023-2039. 10.1016/j.biocel.2008.02.020.View ArticlePubMedGoogle Scholar
- Heineke J, Molkentin JD: Regulation of cardiac hypertrophy by intracellular signaling pathways. Nat Rev Mol Cell Biol. 2006, 7: 589-600. 10.1038/nrm1983.View ArticlePubMedGoogle Scholar
- Molkentin JD: Calcineurin–NFAT signaling regulates the cardiac hypertrophic response in coordination with the MAPKs. Cardiovasc Res. 2004, 63: 467-475. 10.1016/j.cardiores.2004.01.021.View ArticlePubMedGoogle Scholar
- Pikkarainen S, Tokola H, Kerkelä R, Ruskoaho H: GATA transcription factors in the developing and adult heart. Cardiovasc Res. 2004, 63: 196-207. 10.1016/j.cardiores.2004.03.025.View ArticlePubMedGoogle Scholar
- Wilkins BJ, Dai Y-S, Bueno OF, Parsons SA, Jian X, Plank DM, Jones F, Kimball TR, Molkentin JD: Calcineurin/NFAT coupling participates in pathological, but not physiological. Cardiac Hypertrophy Circ Res. 2004, 94: 110-118.View ArticlePubMedGoogle Scholar
- Manukyan I, Galatioto J, Mascareno E, Bhaduri S, Siddiqui MA: Cross-talk between calcineurin/NFAT and Jak/STAT signaling induces cardio protective alphaB-crystallin gene expression in response to hypertrophic stimuli. J Cell Mol Med. 2010, 6B: 1707-1716.Google Scholar
- Sanna B, Bueno OF, Dai YS, Wilkins BJ, Molkentin JD: Direct and indirect interactions between calcineurin-NFAT and MEK1-extracellular signal-regulated kinase 1/2 signaling pathways regulate cardiac gene expression and cellular growth. Mol Cell Biol. 2005, 25: 865-878. 10.1128/MCB.25.3.865-878.2005.View ArticlePubMedPubMed CentralGoogle Scholar
- Kimura TE, Jin J, Zi M, Prehar S, Liu W, Oceandy D, Abe J, Neyses L, Weston AH, Cartwright EJ, Wang X: Targeted deletion of the extracellular signal-regulated protein kinase 5 attenuates hypertrophic response and promotes pressure overload –induced apoptosis in the heart. Circ Res. 2010, 106: 961-970. 10.1161/CIRCRESAHA.109.209320.View ArticlePubMedPubMed CentralGoogle Scholar
- Kodama H, Fukuda K, Pan J, Sano M, Takahashi T, Kato T, Makino S, Manabe T, Murata M, Ogawa S: Significance of ERK cascade compared with JAK/STAT and PI3-K pathway in gp130-mediated cardiac hypertrophy. Am J Physiol Heart Circ Physiol. 2000, 279: H1635-H1644.PubMedGoogle Scholar
- Oakley D: General cardiology: the athlete’s heart. Heart. 2001, 86: 722-726. 10.1136/heart.86.6.722.View ArticlePubMedPubMed CentralGoogle Scholar
- Jefferis BJ, Lawlor DA, Ebrahim S, Wannamethee SG, Feyerabend C, Doig M, McMeekin L, Cook DG, Whincup PH: Cotinine-assessed second-hand smoke exposure and risk of cardiovascular disease in older adults. Heart. 2010, 96: 854-859. 10.1136/hrt.2009.191148.View ArticlePubMedPubMed CentralGoogle Scholar
- Frey PF, Ganz P, Hsue PY, Benowitz NL, Glantz SA, Balmes JR, Schick SF: The exposure-dependent effects of aged secondhand smoke on endothelial function. J Am Coll Cardiol. 2012, 59: 1908-1913. 10.1016/j.jacc.2012.02.025.View ArticlePubMedGoogle Scholar
- Lakatta EG, Yin FC: Myocardial aging: functional alterations and related cellular mechanisms. Am J Physiol. 1982, 242: H927-H941.PubMedGoogle Scholar
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2261/14/195/prepub
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