Left ventricular (LV) pressure (PO) or volume (VO) overload is accompanied by myocardial remodeling, but mechanisms that contribute to this progressive remodeling process remain unclear. The matrix metalloproteinases (MMPs) contribute to tissue remodeling in a number of disease states. This study tested the hypothesis that increased MMP expression and activity occur after the induction of an LV overload, which is accompanied by a loss of endogenous MMP inhibitory control. LV MMP zymographic activity and species abundance were measured in dogs under the following conditions: acute PO induced by ascending aortic balloon inflation (6 h, n = 9), prolonged PO by aortic banding (10 days, n = 5), acute VO through mitral regurgitation secondary to chordal rupture (6 h, n = 6), prolonged VO due to mitral regurgitation (14 days, n = 7), and sham controls (n = 11). MMP zymographic activity in the 92-kDa region, indicative of MMP-9 activity, increased over threefold in acute PO and VO and fell to control levels in prolonged PO and VO. The MMP-9 activity-to-abundance ratio increased by over fourfold with acute VO and twofold in acute PO, suggesting a loss of inhibitory control. Endogenous MMP inhibitor content was unchanged with either PO or VO. Interstitial collagenase (MMP-1) content decreased by 50% with acute VO but not with acute PO. Stromelysin (MMP-3) levels increased by 40% with acute VO and increased by 80% with prolonged PO. Although changes in LV myocardial MMP activity and inhibitory control occurred in both acute and prolonged PO and VO states, these changes were not identical. These results suggest that the type of overload stimulus may selectively influence myocardial MMP activity and expression, which in turn would affect the overall LV myocardial remodeling process in LV overload.

Although lisinopril significantly reduced preload, its effect on LV contractility was insignificant in experimental MR. Conversely, atenolol, when added to lisinopril, achieved maximum hemodynamic benefit and also restored LV contractility.

An adult feline right ventricular pressure overload (RVPO) model was used to examine the two S6 kinase (S6K) isoforms, p70 S6K and p85 S6K , that are involved in translational and transcriptional activation. Biochemical and confocal microscopy analyses at the level of the cardiocyte revealed that p70 S6K is present predominantly in the cytosol, substantially activated in 1-h RVPO (>12 fold), and phosphorylated in the pseudosubstrate domain at the Ser-411, Thr-421, and Ser-424 sites. p85 S6K , which was localized exclusively in the nucleus, showed activation subsequent to p70 S6K , with a sustained increase in phosphorylation for up to 48 h of RVPO at equivalent sites of p70 S6K , Thr-421 and Ser-424, but not at Ser-411. Neither isoform translocated between the cytosol and the nucleus. Further studies to determine potential upstream elements of S6K activation revealed: (i) similar time course of activation for protein kinase C isoforms (␣, ␥, and ⑀) and c-Raf, (ii) absence of accompanying phosphatidylinositol 3-kinase activation, (iii) activation of c-Src subsequent to p70 S6K , and (iv) similar changes in adult cardiocytes after treatment with 12-O-tetradecanoylphorbol-13-acetate. Thus, these studies suggest that a protein kinase C-mediated pathway couples pressure overload to growth induction via differential activation of S6K isoforms in cardiac hypertrophy.Hypertrophic cardiac growth occurs by an increase in cellular mass via a relatively coordinate increase in cellular protein content (1). In the terminally differentiated adult cardiac muscle cell, translational mechanisms have a key role in regulating the rate of protein synthesis during hypertrophic growth. Phosphorylation of the carboxyl terminus of 40 S ribosomal S6 protein (S6 protein) has been shown to regulate protein synthesis rate by mediating protein translational initiation and elongation (2), and a growing number of studies show strong correlation between translational efficiency and S6 protein phosphorylation (3-5). Two distinct families of S6 kinases, p90Rsk (ribosomal S6 kinase) and p70/85 S6 kinase (S6K), 1 appear to be involved in phosphorylation of the S6 protein (2, 6, 7). However, S6K is suggested to be primarily responsible for the S6 protein phosphorylation upon stimulation of cells with insulin and a variety of mitogenic stimuli (8 -10). S6K consists of two isoforms transcribed by a single gene due to alternative splicing: a 70-kDa cytoplasmic isoform (p70 S6K ) and a 85-kDa nuclear isoform (p85 S6K ) with an additional 23 residues at the amino terminus consisting of a putative nuclear targeting sequence (11). Both isoforms are known to phosphorylate the S6 protein and mediate the translation of polypyrimidine tract mRNA, including transcripts of ribosomal proteins and translational elongation factors (12). In addition to playing a role in protein translational control, nuclear p85 S6K has been shown to be important for transcriptional activation (13), increased DNA synthesis, and G 1 to S phase transition (14).For activation, both is...

These and additional corroborative data show that increased cardiocyte microtubule network density is an important mechanism for the ventricular contractile dysfunction that develops in large mammals with adult-onset pressure-overload-induced cardiac hypertrophy.