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Pressure overload-induced LV hypertrophy and dysfunction in mice are exacerbated by congenital NOS3 deficiency

¹Department of Anesthesia and Critical Care, ²Cardiovascular Research Center, ³Cardiac Ultrasound Laboratory in the Cardiology Division of the Department of Medicine, and the ⁴Department of Pathology at the Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114

Submitted 1 October 2003 ; accepted in final form 20 November 2003

	ABSTRACT

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To investigate the role of endothelial nitric oxide synthase (NOS3) in left ventricular (LV) remodeling induced by chronic pressure overload, the impact of transverse aortic constriction (TAC) on LV structure and function was compared in wild-type (WT) and NOS3-deficient (NOS3^–/–) mice. Before TAC, LV wall thickness, mass, and fractional shortening were similar in the two mouse strains. Twenty-eight days after TAC, both WT and NOS3^–/– mice had increased LV wall thickness and mass as well as decreased fractional shortening. Although the pressure gradient across the TAC was similar in both strains of mice 28 days after TAC, LV mass and posterior wall thickness were greater in NOS3^–/– than in WT mice, whereas fractional shortening and the maximum rate of developed LV pressure were less. Diastolic function, as measured by the time constant of isovolumic relaxation and the maximum rate of LV pressure decay, was impaired to a greater extent in NOS3^–/– than in WT mice. The degree of myocyte hypertrophy and LV fibrosis was greater in NOS3^–/– than in WT mice at 28 days after TAC. Mortality was greater in NOS3^–/– than in WT mice 28 days after TAC. Long-term administration of hydralazine normalized the blood pressure and prevented the LV dilation in NOS3^–/– mice but did not prevent the LV hypertrophy, dysfunction, and fibrosis associated with NOS3 deficiency after TAC. These results suggest that the absence of NOS3 augments LV dysfunction and remodeling in a murine model of chronic pressure overload.

heart failure; remodeling

Nitric oxide (NO) modulates many of the processes leading to ventricular remodeling. In clinical studies, long-term administration of nitrates was found to limit LV remodeling after MI (14). Endothelium-derived NO causes systemic vascular relaxation (4), thereby reducing both cardiac preload and afterload. Recent evidence suggests that NO can decrease cardiac fibrosis (7, 25) and angiotensin II-induced cardiac myocyte hypertrophy (20) as well as increase angiogenesis (17), all of which can limit ventricular remodeling.

Three NO synthase (NOS) isoforms (NOS1, NOS2, and NOS3) are responsible for NO synthesis in the mammalian heart. Scherrer-Crosbie et al. (22) recently reported studies in mice on the role of NOS3 in the LV remodeling that occurs after MI. They found that coronary artery ligation induced greater LV dysfunction, dilation, and hypertrophy in NOS3-deficient (NOS3^–/–) mice than in wild-type (WT) mice, associated with increased myocyte hypertrophy in the myocardium remote from infarction.

To determine whether or not NOS3 deficiency has a deleterious effect on LV remodeling induced by hemodynamic stresses other than MI, we compared the changes in LV size and function in WT and NOS3^–/– mice after pressure overload induced by transverse aortic constriction (TAC). We report that NOS3 deficiency augments LV remodeling in response to prolonged pressure overload in mice.

	METHODS

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Experimental protocol. All animal procedures were conducted in accordance with guidelines published in the Guide for the Care and Use of Laboratory Animals (National Research Council, National Academy Press, Washington, DC, 1996) and approved by the Massachusetts General Hospital Subcommittee on Research Animal Care.

We studied 2- to 4-mo-old male C57BL/6J WT mice and male NOS3^–/– mice, backcrossed 10 generations onto a C57BL/6J background. In additional experiments, NOS3^–/– mice were treated with hydralazine (250 mg/l of drinking water) starting 2 wk before TAC until the conclusion of the experiment.

To induce pressure overload, the thoracic aorta was tied between the right inominate and the left carotid arteries against a 27-gauge needle with 7-0 nylon suture followed by removal of the needle (21).

Serial echocardiographic measurements. Transthoracic echocardiograms were obtained using a 13-MHz probe (Vivid 5, GE Medical Systems; Boston, MA) in sedated mice (ketamine 50 µg/g ip) before and 7, 15, and 28 days after TAC, as described previously (22). Serial echocardiographic measurements at all four time points were obtained and reported in 19 WT mice, 14 NOS3^–/– mice, and 17 NOS3^–/– mice treated with hydralazine. Heart rate (HR), LV end-diastolic internal diameter (LVID_ED), and LV posterior wall thickness (PWT) were measured, and the LV fractional shortening (FS) was calculated by using an M-Mode echocardiogram obtained at the midpapillary level. LV end-diastolic and end-systolic volumes were calculated as described previously (26). Cardiac output was calculated as the HR times the difference between LV end-diastolic and end-systolic volumes.

Invasive hemodynamics. Hemodynamic measurements were obtained using a 1.4-Fr high-fidelity Millar pressure catheter in anesthetized mice (fentanyl 250 ng/g and ketamine 50 µg/g ip) as described previously (22), in mice not subjected to TAC (4 WT, 5 NOS3^–/–, and 4 NOS3^–/– treated with hydralazine), in mice 7 days after TAC (13 WT and 4 NOS3^–/–, and 5 NOS3^–/– treated with hydralazine), and in mice 28 days after TAC (14 WT, 7 NOS3^–/–, and 12 NOS3^–/– treated with hydralazine). The mice that were studied 28 days after TAC were also examined serially with echocardiography as described above.

Histological analysis. After the invasive hemodynamic measurements were performed, mice were euthanized, and the left ventricle was blotted, weighed, and embedded in paraffin. Five-micrometerthick sections were obtained at midventricular level and stained with Miller's elastin stain and hematoxylin. Myocyte width was measured in mice 28 days after TAC. Twenty measurements were obtained at the level of the nucleus in longitudinally sectioned myocytes in each section (viewed at a magnification of x200).

Myocardial interstitial fibrosis was assessed at baseline and 7 and 28 days after TAC on midventricular sections stained with Sirius red. Five fields per section excluding large vessels were digitized at a magnification of x100. The area of collagen deposition indicated by red staining was outlined and quantitated by an automated image analysis program (IP Lab Spectrum, Signal Analytics; Vienna VA), and the ratio of the area of collagen deposition to the total myocardial area was calculated. Staining, scanning, and quantitation were all performed by a blinded observer.

Statistical analysis. All data are expressed as means ± SE. Data were analyzed using ANOVA for repeated measures with mixed effects models or two-way ANOVA with the SAS statistical software package (Cary, NC). P values were adjusted using Scheffé's method. An analysis of survival rates after TAC was performed with the Log-Rank test. P < 0.05 was considered significant.

	RESULTS

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Serial echocardiographic measurements. Before TAC, the LV dimensions and systolic function, measured by employing echocardiography, were similar in WT and NOS3^–/– mice (Table 1). TAC increased LVID_ED in NOS3^–/– mice 28 days after TAC (P < 0.05) but not in WT mice. Although TAC decreased FS in both genotypes (P < 0.05 for both; Table 1), the reduction of FS was more marked in NOS3^–/– mice than in WT mice starting 7 days after TAC (P = 0.0002; Table 1). Although PWT increased in both genotypes (P < 0.05 for both; Table 1), PWT was greater in NOS3^–/– mice than in WT mice 7 and 28 days after TAC (P = 0.006). Cardiac output, measured by echocardiography contemporaneous with the hemodynamic measurements 28 days after TAC, did not differ between the genotypes (Table 1).

Hemodynamic measurements. In mice not subjected to TAC, measures of LV systolic and diastolic function did not differ significantly between the genotypes (Table 2). After TAC, the transstenotic systolic pressure gradient (the difference between the right and left carotid artery pressure) was similar in WT and NOS3^–/– mice on day 7 and 28 after TAC (Table 2). However, LV end-systolic pressure was lower in NOS3^–/– mice than in WT mice 28 days after TAC (P < 0.05, Table 2). The maximum rate of developed LV pressure and the maximum rate of pressure decay (dP/dt_max and dP/dt_min, respectively) were similar in both genotypes 7 days after TAC but were impaired to a greater extent in NOS3^–/– than in WT mice (P < 0.01 for both) on day 28 after TAC. LV end-diastolic pressure was higher in NOS3^–/– mice than in WT mice 28 days after TAC (P < 0.05, Table 2). The time constant of isovolumic relaxation () was more prolonged in NOS3^–/– mice (P < 0.01, Table 2) on day 28 after TAC.

LV weight. LV weight-to-body weight ratios did not differ between the two strains of mice without TAC. Seven and 28 days after TAC, the LV weight-to-body weight ratio was greater in NOS3^–/– mice than in WT mice (P < 0.05 for both, Table 3).

Impact of pharmacological reduction of afterload on LV remodeling in NOS3^–/– mice. As we previously reported (22), systolic blood pressure was greater in awake NOS3^–/– mice than in WT mice, and hydralazine treatment for 2 wk decreased the systolic blood pressure in NOS3^–/– mice to the level observed in WT mice. Systolic arterial pressure measured in the left carotid artery (SAP_L) was decreased by hydralazine treatment in NOS3^–/– mice before and 7 days after TAC (P < 0.05 for both, Table 2). There was no difference in SAP_L between WT mice and hydralazine-treated NOS3^–/– mice throughout the experimental period. Hydralazine treatment prevented LV dilatation in NOS3^–/– mice subjected to TAC (P < 0.01, Table 1). However, hydralazine failed to attenuate the greater increase in PWT or more marked decrease in dP/dt_max associated with NOS3 deficiency after TAC (Tables 1 and 2). When compared with WT mice 28 days after TAC, diastolic function remained impaired in hydralazine-treated NOS3^–/– mice, as reflected by a greater and a lower dP/dt_min (P < 0.05 for both).

Myocyte size. Twenty-eight days after TAC, myocyte width was less in WT mice than in NOS3^–/– mice with or without hydralazine treatment (P < 0.05 for both, Table 3 and Fig. 1).

View larger version (113K): [in this window] [in a new window]   Fig. 1. Myocyte width in the left ventricular (LV) myocardium in wild-type (WT) and NOS3-deficient (NOS3–/–) mice at 28 days after transverse aortic constriction (TAC). Myocyte nuclei (yellow arrows) were stained with hematoxylin. Myocyte width at the level of the nucleus (shown between white arrows) was greater in NOS3–/– than in WT mice.

Myocardial fibrosis. In mice without TAC, the area of collagen deposition was <0.5% of the total myocardial area in both genotypes (Table 3). Seven and 28 days after TAC, the area of myocardial fibrosis markedly increased in NOS3^–/– mice with or without hydralazine treatment (P < 0.05 values differ from before TAC in both treated and untreated NOS3^–/– mice, Table 3, Fig. 2B), but there was no increase of myocardial fibrosis in WT mice (Table 3, Fig. 2A). Collagen deposition was distributed heterogeneously throughout the myocardium, and both interstitial fibrosis and foci of replacement fibrosis were observed (Fig. 2C).

View larger version (62K): [in this window] [in a new window]   Fig. 2. Collagen deposition (red staining) in the LV of WT (A) and NOS3–/– (B) mice 28 days after TAC. Twenty-eight days after TAC, myocardial collagen deposition was increased in NOS3–/– compared with WT mice. C: representative section with replacement fibrosis in NOS3–/– mice 28 days after TAC. Magnification of the pictures are x10 for A and B and x100 for C.

Survival after TAC. Survival rate was examined in mice that survived longer than 24 h after TAC to exclude the possible impact of NOS3 deficiency on perioperative mortality. The survival rate was higher for WT than in NOS3^–/– mice 28 days after TAC (Fig. 3). Whereas no mice died in the WT group, 4 of 25 NOS3^–/– mice died (P < 0.05 vs. WT). In those mice that died before completion of the study, the last echocardiography performed before death at 7 or 15 days after TAC showed decreased shortening fraction (25 ± 3%, P < 0.01 vs. surviving mice of all strains at day 15) and dilated LV (LVID_ED = 4.2 ± 0.1 mm, P < 0.001 vs. surviving mice of all strains at day 15).

View larger version (13K): [in this window] [in a new window]   Fig. 3. Survival of WT mice, NOS3–/–, and NOS3–/– mice treated with hydralazine (NOS3–/– H). Survival was less in untreated NOS3–/– mice than in WT mice (*P < 0.05).

	DISCUSSION

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The present study demonstrates that NOS3 deficiency augments LV remodeling and dysfunction in a murine model of LV chronic pressure overload. Before TAC, LV dimensions and contractile function did not differ between WT and NOS3^–/– mice, confirming previous reports (5). However, 28 days after TAC, LV remodeling and dysfunction were more pronounced in NOS3^–/– mice than in WT mice. The LVID_ED was increased in NOS3^–/– mice 28 days after TAC but was unchanged in WT mice. Although FS was decreased in both genotypes, FS was reduced to a greater extent in NOS3^–/– mice than in WT mice. After 28 days of TAC, invasive hemodynamic measurements revealed greater impairment of systolic and diastolic function in NOS3^–/– mice compared with WT mice. The deleterious effects of NOS3 deficiency were associated with excess myocyte hypertrophy and LV fibrosis. The presence of NOS3 conferred a survival advantage 28 days after TAC.

Probably because NOS3^–/– mice have hypertension (22), TAC may place a greater afterload on the LV of NOS3^–/– mice than on that of WT mice. Of note, at 28 days after TAC, LV end-systolic pressure was less in NOS3^–/– mice than in WT mice, which is likely further evidence of greater LV dysfunction in NOS3^–/– mice. To examine the impact of NOS3 deficiency on LV remodeling without the confounding effects of the elevated blood pressure seen in NOS3^–/– mice, we included a group of NOS3^–/– mice that were treated with hydralazine to normalize blood pressure. Normalization of systemic blood pressure with hydralazine prevented LV dilation in NOS3^–/– mice (Table 1). LV end-systolic pressure measurements obtained 7 days after TAC suggest that LV afterload was greater in untreated NOS3^–/– mice than in hydralazine-treated NOS3^–/– mice (P = 0.06, Table 2). It is probable that the beneficial effect of hydralazine on LV remodeling in NOS3^–/– mice was attributable to its ability to decrease systemic blood pressure leading to a decreased LV afterload. In contrast, although LV end-systolic pressure in hydralazine-treated NOS3^–/– mice were equal to those in WT mice at 7 and 28 days after TAC (Table 2), the greater changes in posterior LV wall thickness, LV dP/dt, , myocyte hypertrophy, and cardiac fibrosis observed in untreated NOS3^–/– mice after TAC were not prevented by hydralazine. These results suggest that deleterious effects of NOS3 deficiency after TAC are not attributable exclusively to hypertension seen in NOS3^–/– mice.

We previously reported that LV remodeling after occlusion of the left anterior descending coronary artery was more marked in NOS3^–/– mice than in WT mice, associated with increased myocyte hypertrophy in the myocardium remote from the MI (22). In contrast, Liu and colleagues (13) found that LV remodeling did not differ in NOS3^–/– mice and WT mice with large MIs, but that inhibition of angiotensin-converting enzyme or of angiotensin 2 receptor signaling attenuated LV remodeling only in the latter. The observations in mice subjected to TAC presented here provide further support for the role of NOS3 in attenuating LV remodeling in response to a spectrum of hemodynamic challenges.

The extensive cardiac fibrosis found after TAC in NOS3^–/– mice with or without hydralazine treatment (but not in WT mice) was unexpected. In our previous study of NOS3^–/– mice subjected to left anterior descending coronary artery occlusion, we did not detect a marked increase in fibrosis in the remote myocardium (data not shown). It is probable that at least a component of the LV contractile dysfunction seen in NOS3^–/– mice subjected to TAC could be attributed to this fibrotic process (1, 8).

NO, in part via activation of cGMP synthesis by soluble guanylate cyclase, is known to inhibit hypertrophy of cardiac myocytes and proliferation of cardiac fibrobasts in culture (2). Cardiac-specific overexpression of NOS3 attenuates the LV hypertrophy induced by chronic isoproterenol infusion (19) or by left anterior descending occlusion (9). Of note, mice deficient in natriuretic peptide receptor A (Npr1), a particulate guanylate cyclase, have cardiac hypertrophy and fibrosis (18), and TAC induced marked LV dysfunction in Npr1^–/– mice but not in WT mice (11). In addition, mice deficient in brain natriuretic peptide (Nppb^–/–) have multifocal cardiac fibrosis, and these fibrotic lesions increase in size and number in response to TAC (23). Interestingly, although both Npr1^–/– mice and Nppb^–/– mice had increased cardiac fibrosis at baseline, NOS3^–/– mice developed cardiac fibrosis only after TAC. Nonetheless, the observations that NOS3, the natriuretic peptide receptor A, and brain natriuretic peptide all attenuate LV hypertrophy and/or fibrosis induced by TAC suggest an important role for cGMP in limiting LV remodeling.

Although TAC caused no mortality in WT mice, 16% of NOS3^–/– mice died by 28 days after TAC. Although precise causes of death are unknown, the last echocardiogram before death showed markedly decreased shortening fraction and dilated LV compared with those of the surviving mice. These results suggest early onset of LV failure as the cause of death in those mice.

The present study has important clinical implications. Increased LV afterload, such as that caused by systemic hypertension, is a major cause of heart failure and cardiac death. In hypertensive patients, ventricular remodeling, as reflected by an augmentation of the LV mass, is an independent predictor of cardiovascular events (6, 12). Moreover, regression of LV hypertrophy using angiotensin-converting enzyme inhibitors (15) or other antihypertensive agents (24) may reduce the risk of death or heart failure in a manner that is independent of any reduction in blood pressure. Our results highlight the importance of NOS3 in preventing LV dysfunction and mortality in mice subjected to sustained pressure overload possibly by limiting cardiac myocyte hypertrophy and fibrosis. If findings in mice can be extrapolated to human beings, we speculate that individuals with congenital or acquired deficiencies of NOS3 activity may be at increased risk of deleterious LV remodeling in response to systemic hypertension or other hemodynamic challenges (10, 16). Moreover, strategies designed to augment cardiac NOS3 expression and/or activity may prevent LV remodeling and associated cardiovascular morbidity and mortality with chronic pressure overload.

	ACKNOWLEDGMENTS

 
The authors thank Dr. W. M. Zapol for valuable comments, Dr. P. L. Huang for advice on tail-cuff pressure measurements, Dr. S. Houser for help with the pathological techniques, Dr. Yuchiao Chang for statistical advice, A. Branaghan for laboratory technical assistance, and L. Cral and R. Flynn for technical help with the ultrasound equipment.

GRANTS

This study was supported by a Research Fellowship from the American Society of Echocardiography (to M. Scherrer-Crosbie), a Scientist Development Grant from the American Heart Association (to M. Scherrer-Crosbie),and National Heart, Lung, and Blood Institute Grants HL-42397, HL-57172, and HL-70896.

	FOOTNOTES

 

Address for reprint requests and other correspondence: F. Ichinose, Dept. of Anesthesia and Critical Care, Massachusetts General Hospital, 55 Fruit St., Boston, MA 02114 (E-mail: ichinose{at}etherdome.mgh.harvard.edu).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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