Abstract 265: Systemic Inflammation and Cardiac Macrophage Infiltration Accompany Stretch-induced Myocardial Injury in Swine Subjected to Transient Pressure Overload

Objective: Transient pressure overload (TPO) elicits stretch-induced myocyte injury in the absence of ischemia or infarction, but the extent to which this is associated with inflammation is unclear. The present study was designed to assess immune activation after TPO in swine and compare the inflammatory cytokine profile to that observed after myocardial infarction (MI). Methods: Swine received a brief infusion of phenylephrine (18 mg/hr iv; 30-60 min) to induce TPO and were studied for 1 hr (n=5), 3 hr (n=6), or 24 hr (n=6) before analysis of myocardial macrophage gene expression (CD68) via qPCR. Serial blood sampling was performed to assess neutrophil and monocyte counts as well as circulating cardiac troponin I (cTnI), IL-6, TNF-α, and CRP. Cytokine levels were compared to those from a separate group (n=5) subjected to a 60 min LAD occlusion to produce MI. Results: TPO increased circulating cTnI (from 20±5 ng/L to 340±58 ng/L at 3 hr and 1520±616 ng/L at 24 hr; p<0.01) without evidence of infarction. Compared with controls (n=6), swine subjected to TPO exhibited increased CD68 gene expression at 1, 3, and 24 hr ( A ). This was accompanied by a rise in peripheral blood neutrophils and monocytes ( B ) as well as an elevation in circulating IL-6, TNF-α, and CRP that was comparable to that observed after MI ( C ). Conclusion: Myocyte injury following TPO elicits mobilization of neutrophils and monocytes and a rise in circulating inflammatory cytokines comparable to that observed after MI. This is accompanied by an increase in cardiac macrophages and may be an important mechanism by which repetitive episodes of TPO lead to interstitial fibrosis and diastolic dysfunction without anatomic hypertrophy.

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Abstract 100: An Altered Epigenomic Mark Predisposes to Dilated Cardiomyopathy Through Alternative Splicing of Sarcomeric Gene Expression in Mice

Circulation Research ◽

10.1161/res.111.suppl_1.a100 ◽

2012 ◽

Vol 111 (suppl_1) ◽

Author(s):

Ana Vujic ◽

Emma Robinson ◽

Mitsutero Ito ◽

Syed Haider ◽

Jeremy Skepper ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Dilated Cardiomyopathy ◽

Dna Methyltransferase ◽

Complex Disease ◽

Interstitial Fibrosis ◽

Pressure Overload ◽

Hypertrophic Response ◽

Sarcomeric Gene ◽

End Stage

Distinct epigenomic patterns of DNA methylation exist in important elements of the cardiac genome in human end-stage cardiomyopathy but whether these contribute to disease progression is unknown. We examined and found that the main DNA methyltransferase expressed in the adult mammalian heart is DNMT3B. We therefore generated a conditional inducible Dnmt3b knockout mouse to test the effect of altered DNA methylation in the heart. Upon induction in the adult mouse, Dnmt3b knockout (CKO) led rapidly to severe systolic insufficiency and myocardial thinning. Examination of myocyte nuclei reflected a loss of homogeniety and re-distribution of heterochromatin. This was accompanied by widespread myocardial interstitial fibrosis and myofibrillary disarray. We examined the myocardial transcriptome of CKO mice by RNA-seq and discovered significant changes in levels of transcript splicing isoforms especially those of sarcomeric genes. When subjected to pressure overload, CKO mice failed to mount a compensatory hypertrophic response and instead developed accelerated fulminant dilated cardiomyopathy. Our results demonstrate that DNA methylation has a distinct role with regulating transcript isoform splicing apart from gene expression. In particular, we have highlighted a mechanism by which the epigenome may mediate the development and progression of a complex disease.

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Regression of pressure overload-induced left ventricular hypertrophy in mice

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00836.2004 ◽

2005 ◽

Vol 288 (6) ◽

pp. H2702-H2707 ◽

Cited By ~ 56

Author(s):

Xiao-Ming Gao ◽

Helen Kiriazis ◽

Xiao-Lei Moore ◽

Xin-Heng Feng ◽

Karen Sheppard ◽

...

Keyword(s):

Gene Expression ◽

Time Course ◽

Interstitial Fibrosis ◽

Gene Expression Pattern ◽

Pressure Overload ◽

Left Ventricular ◽

Matrix Metalloproteinase 2 ◽

Aortic Banding ◽

Genetic Components ◽

Collagen Iii

As a prelude to investigating the mechanism of regression of pressure overload-induced left ventricular (LV) hypertrophy (LVH), we studied the time course for the development and subsequent regression of LVH as well as accompanying alterations in cardiac function, histology, and gene expression. Mice were subjected to aortic banding for 4 or 8 wk to establish LVH, and regression was initiated by release of aortic banding for 6 wk. Progressive increase in LV mass and gradual chamber dilatation and dysfunction occurred after aortic banding. LVH was also associated with myocyte enlargement, interstitial fibrosis, and enhanced expression of atrial natriuretic peptide, collagen I, collagen III, and matrix metalloproteinase-2 but suppressed expression of α-myosin heavy chain and sarcoplasmic reticulum Ca2+-ATPase. Aortic debanding completely or partially reversed LVH, chamber dilatation and dysfunction, myocyte size, interstitial fibrosis, and gene expression pattern, each with a distinct time course. The extent of LVH regression was dependent on the duration of pressure overload, evidenced by the fact that restoration of LV structure and function was complete in animals subjected to 4 wk of aortic banding but incomplete in animals subjected to 8 wk of aortic banding. In conclusion, LVH regression comprises a variety of morphological, functional, and genetic components that show distinct time courses. A longer period of pressure overload is associated with a slower rate of LVH regression.

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Pregnancy mitigates cardiac pathology in a mouse model of left ventricular pressure overload

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00056.2016 ◽

2016 ◽

Vol 311 (3) ◽

pp. H807-H814 ◽

Cited By ~ 5

Author(s):

Hong Xu ◽

Elza D. van Deel ◽

Mark R. Johnson ◽

Petra Opić ◽

Bronwen R. Herbert ◽

...

Keyword(s):

Gene Expression ◽

Heart Disease ◽

Interstitial Fibrosis ◽

Experimental Studies ◽

Pressure Overload ◽

Left Ventricular Pressure ◽

Capillary Density ◽

Left Ventricular ◽

Lv Function ◽

Lung Weight

In Western countries heart disease is the leading cause of maternal death during pregnancy. The effect of pregnancy on the heart is difficult to study in patients with preexisting heart disease. Since experimental studies are scarce, we investigated the effect of pressure overload, produced by transverse aortic constriction (TAC) in mice, on the ability to conceive, pregnancy outcome, and maternal cardiac structure and function. Four weeks of TAC produced left ventricular (LV) hypertrophy and dysfunction with marked interstitial fibrosis, decreased capillary density, and induced pathological cardiac gene expression. Pregnancy increased relative LV and right ventricular weight without affecting the deterioration of LV function following TAC. Surprisingly, the TAC-induced increase in relative heart and lung weight was mitigated by pregnancy, which was accompanied by a trend towards normalization of capillary density and natriuretic peptide type A expression. Additionally, the combination of pregnancy and TAC increased the cardiac phosphorylation of c-Jun, and STAT1, but reduced phosphoinositide 3-kinase phosphorylation. Finally, TAC did not significantly affect conception rate, pregnancy duration, uterus size, litter size, and pup weight. In conclusion, we found that, rather than exacerbating the changes associated with cardiac pressure overload, pregnancy actually attenuated pathological LV remodeling and mitigated pulmonary congestion, and pathological gene expression produced by TAC, suggesting a positive effect of pregnancy on the pressure-overloaded heart.

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CaMKII inhibition in heart failure, beneficial, harmful, or both

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00812.2011 ◽

2012 ◽

Vol 302 (7) ◽

pp. H1454-H1465 ◽

Cited By ~ 20

Author(s):

Jun Cheng ◽

Lin Xu ◽

Dongwu Lai ◽

Arnaud Guilbert ◽

Hyun Joung Lim ◽

...

Keyword(s):

Heart Failure ◽

Diastolic Function ◽

Troponin I ◽

Interstitial Fibrosis ◽

Pressure Overload ◽

Inactivation Kinetics ◽

Adrenergic Stimulation ◽

Adrenergic Regulation ◽

Cardiac Reserve

Calmodulin-dependent protein kinase II (CaMKII) has been proposed to be a therapeutic target for heart failure (HF). However, the cardiac effect of chronic CaMKII inhibition in HF has not been well understood. We have tested alterations of Ca2+ handling, excitation-contraction coupling, and in vivo β-adrenergic regulation in pressure-overload HF mice with CaMKIIδ knockout (KO). HF was produced in wild-type (WT) and KO mice 1 wk after severe thoracic aortic banding (sTAB) with a continuous left ventricle (LV) dilation and reduction of ejection fraction for up to 3 wk postbanding. Cardiac hypertrophy was similar between WT HF and KO HF mice. However, KO HF mice manifested exacerbation of diastolic function and reduction in cardiac reserve to β-adrenergic stimulation. Compared with WT HF, L-type calcium channel current ( ICa) density in KO HF LV was decreased without changes in ICa activation and inactivation kinetics, whereas ICa recovery from inactivation was accelerated and Ca2+-dependent ICa facilitation, a positive staircase blunted in WT HF, was recovered. However, ICa response to isoproterenol was reduced. KO HF myocytes manifested dramatic decrease in sarcoplasmic reticulum (SR) Ca2+ leak and slowed cytostolic Ca2+ concentration decline. Sarcomere shortening was increased, but relaxation was slowed. In addition, an increase in myofilament sensitivity to Ca2+ and the slow skeletal muscle troponin I-to-cardiac troponin I ratio and interstitial fibrosis and a decrease in Na/Ca exchange function and myocyte apoptosis were observed in KO HF LV. CaMKIIδ KO cannot suppress severe pressure-overload-induced HF. Although cellular contractility is improved, it reduces in vivo cardiac reserve to β-adrenergic regulation and deteriorates diastolic function. Our findings challenge the strategy of CaMKII inhibition in HF.

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Isoproterenol infusion induces alterations in expression of hypertrophy-associated genes in rat heart

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1995.269.2.h638 ◽

1995 ◽

Vol 269 (2) ◽

pp. H638-H647 ◽

Cited By ~ 28

Author(s):

M. O. Boluyt ◽

X. Long ◽

T. Eschenhagen ◽

U. Mende ◽

W. Schmitz ◽

...

Keyword(s):

Gene Expression ◽

Transforming Growth Factor ◽

Interstitial Fibrosis ◽

Weight Ratio ◽

Pressure Overload ◽

Tgf Beta ◽

Mrna Accumulation ◽

Expression Of Genes ◽

Male Wistar Rats ◽

Cardiac Gene

Chronic infusion of isoproterenol (Iso) in rats results in cardiac hypertrophy via incompletely understood mechanisms. Our purpose was to determine whether Iso infusion would alter the expression of genes associated with hypertrophy. Male Wistar rats received either 2.4 mg Iso.kg-1.day-1, 9.9 mg propranolol (Prop).kg-1.day-1, both Iso and Prop, or vehicle (NaCl) via subcutaneously implanted osmotic pumps. In Iso-treated rats, the ventricular weight-to-body weight ratio was increased by 27% after 1 day and peaked on day 3 (+ 40%). Levels of atrial natriuretic factor (ANF) and fibronectin (FN) mRNA in the left ventricles were elevated 20-fold and 13-fold in Iso-treated rats, respectively, peaking at 3 days of infusion. The increase in FN mRNA accumulation was at least partially accounted for by elevated expression of extra type IIIA and IIIB (EIIIA and EIIIB) splicing variants. Levels of transforming growth factor (TGF)-beta 1 mRNA were elevated twofold after 3 days of Iso infusion. The abundance of skeletal alpha-actin (SK) mRNA increased fourfold after 1 day of Iso and declined thereafter. Iso infusion decreased sarcoplasmic reticulum Ca(2+)-ATPase (SERCA) and preproenkephalin (PNK) gene expression by approximately 50% and induced a myosin heavy chain (MHC) isogene switch favoring beta-MHC. Prop partially inhibited the Iso-evoked increases in ANF and FN mRNA, completely prevented the Iso-induced changes in TGF-beta 1 and SERCA mRNA, but had no effect on the Iso-stimulated changes in SK and PNK gene expression. These results demonstrate that chronic Iso infusion elicits alterations in cardiac gene expression that are consistent with the development of myocyte hypertrophy and interstitial fibrosis and are directionally identical to those previously reported for pressure overload hypertrophy.

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