Cardiomyocyte-Specific Overexpression of Nitric Oxide Synthase 3 Improves Left Ventricular Performance and Reduces Compensatory Hypertrophy After Myocardial Infarction

Abstract

Abstract-Nitric oxide (NO) is an important modulator of cardiac performance and left ventricular (LV) remodeling after myocardial infarction (MI). We tested the effect of cardiomyocyte-restricted overexpression of one NO synthase isoform, NOS3, on LV remodeling after MI in mice. LV structure and function before and after permanent LAD coronary artery ligation were compared in transgenic mice with cardiomyocyte-restricted NOS3 overexpression (NOS3-TG) and their wild-type littermates (WT). Before MI, systemic hemodynamic measurements, echocardiographic assessment of LV fractional shortening (FS), heart weight, and myocyte width (as assessed histologically) did not differ in NOS3-TG and WT mice. The inotropic response to graded doses of isoproterenol was significantly reduced in NOS3-TG mice. One week after LAD ligation, the infarcted fraction of the LV did not differ in WT and NOS3-TG mice (34Ϯ4% versus 36Ϯ12%, respectively). Four weeks after MI, however, end-systolic LVID was greater, and fractional shortening and maximum and minimum rates of LV pressure development were less in WT than in NOS3-TG mice. LV weight/body weight ratio was greater in WT than in NOS3-TG mice (5.3Ϯ0.2 versus 4.6Ϯ0.5 mg/g; PϽ0.01). Myocyte width in noninfarcted myocardium was greater in WT than in NOS3-TG mice (18.8Ϯ2.0 versus 16.6Ϯ1.6 m; PϽ0.05), whereas fibrosis in noninfarcted myocardium was similar in both genotypes. Cardiomyocyte-restricted overexpression of NOS3 limits LV dysfunction and remodeling after MI, in part by decreasing myocyte hypertrophy in noninfarcted myocardium. remodeling occurs as an adaptive process by which the myocardium changes shape, size, and function in response to increased mechanical and neurohumoral stress. These adaptations include scar maturation and both eccentric and concentric hypertrophy of remote myocardium to compensate for myocardial loss and increase in wall stress. 1 In case of insufficient compensation, LV remodeling becomes maladaptive leading to ventricular dilatation, overt heart failure, and compromised survival. 2 Nitric oxide (NO) modulates many processes contributing to LV performance including ventricular compliance, myocardial preload and afterload, reperfusion injury, [3][4][5] and angiogenesis. 6 NO may stimulate new vessel recruitment in ischemic myocardium, 7 reduce excessive myocyte hypertrophy, and limit extracellular matrix deposition and myocardial fibrosis. 8,9 NO is generated by three NO synthase isoforms, neuronal NOS1, inducible NOS2, and endothelial NOS3. In cardiac myocytes, NOS3 is targeted to caveolae 10,11 where compartmentalization with ␤-adrenergic receptors and L-type Ca 2ϩ channels allows NO to inhibit ␤-adrenergic-induced inotropy. 12 Neuronal NO synthase (NOS1) is localized to cardiac sarcoplasmic reticulum and modulates myocardial contractility via intracellular calcium cycling. 13,14 Increased cardiac NOS1-derived NO production has been suggested to play an important autocrine regulatory role to maintain myocardial contractility after MI in aging rats. 15 We...

Structural remodelling of cardiomyocytes in the border zone of infarcted rabbit heart

“…A significant increase in cell width was measured in vacuolated CM's and in CM's of the adjacent non-infarcted regions in comparison with the CM's of the remote zone. This observation is consistent with the findings of myocyte hypertrophy in non-infarcted myocardium of small animals after coronary ligation [25,26].…”

Cardiomyocyte‐restricted over‐expression of C‐type natriuretic peptide prevents cardiac hypertrophy induced by myocardial infarction in mice

“…The importance of the CNP/NPRB axis is furthermore illustrated by a series of studies about nitric oxide synthase, supporting the concept that cGMP, a second messenger not stimulated by interaction of CNP with NPRC, is a key player in the local regulation of cardiac remodelling and function after myocardial infarction [36][37][38][39].…”

Endothelial nitric oxide synthase decreases β-adrenergic responsiveness via inhibition of the L-type Ca2+ current

“…A study found that, after chronic pressure overload, NOS3 Ϫ/Ϫ mice had increased hypertrophy, fibrosis, and contractile dysfunction compared with WT mice (41). In addition, mice with cardiac myocyte-specific NOS3 overexpression had limited hypertrophy and contractile dysfunction after pressure overload and myocardial infarction (10,23). Furthermore, it is known that I Ca plays a role in hypertrophy (14).…”

“…For example, mice with specific knockout of NOS3 (NOS3 Ϫ/Ϫ ) have an increased response to ␤-AR stimulation (4,11,19,20,47). Similarly, transgenic mice with cardiac myocyte-specific NOS3 overexpression have a decreased response to ␤-AR stimulation (9,23). Although the vast majority of studies found the above effects, it should be noted that a few studies observed dissimilar results (29,46).…”