The role of L- and D-isomers of homocysteine (Hcy) in vascular versus endocardial endothelial (EE) remodeling and function is not well understood. The hypothesis is that Hcy decreases EE cell density by activating matrix metalloproteinase (MMP) and by inducing left ventricular hypertrophy (LVH) in homocysteinemic hypertensive rats (HHR). And L- and D-isomers of Hcy have differential effects in vessel and myocardium. We used: 1) spontaneously hypertensive rats (SHR) in which endogenous total homocyst(e)ine (tHcy) levels are moderately high (18 micromol/L); 2) control age- and sex-matched normotensive Wistar rats (NWR) in which tHcy levels are normal (4 micromol/L); to create hyperhomocyst(e)inemia, 32 mg/day Hcy was administered for 12 weeks in 3) SHR (SHR-H), and in 4) NWR (NWR-H) rats; 5) endogenous tHcy levels were reduced (from 18 to 12 micromol/L) in SHR by folic acid administration (SHR-F). Plasma tHcy levels were measured by HPLC and spectrophometric methods. The MMP activity, measured by zymography, is increased by chronic Hcy administration, and folic acid treatment decreases MMP activity. The collagen and transforming growth factor-beta1 (TGF-beta1), measured by reverse transcriptase-polymerase chain reaction, are increased by Hcy. Folic acid treatment decreases collagen expression and increases TGF-beta1. In vivo LV function was measured in anesthetized rats by a catheter in the left ventricle. The partial decrease in tHcy levels and no change in arterial pressure in SHR after folic acid administration, suggested that folic acid decreases one of the L- or D-isomer of Hcy, which is not responsible for an increase in arterial pressure, but may be responsible for myocardial dysfunction. The chronic Hcy administration decreases EE function in NWR and SHR. The treatment of folic acid in SHR improves LVH and EE function. Folic acid improves cardiac remodeling and EE function by decreasing one of the D- or L-isomer of Hcy and by decreasing MMP activity in HHR. These results may suggest a differential role of L- and D-isomers in vascular versus cardiac remodeling.
Hyperhomocyst(e)inemia has been associated with the development of hypertension, stroke, and cardiovascular, cerebral/neuronal, renal, and liver diseases. To test the hypothesis that homocyst(e)ine plays an integrated role in multiorgan injury in hypertension, we employed: (1) spontaneously hypertensive rats (SHR) in which endogenous homocyst(e)ine levels are moderately high (18.1 +/- ().5 microM); (2) control age- and sex-matched Wistar Kyoto (WKY) rats in which homocyst(e)ine levels are normal (3.7 +/- 0.3 microM). To create the pathophysiological condition of hyperhomocyst(e)inemia, 20 mg/day homocyst(e)ine was administered for 12 weeks in (3) SHR (SHR-H) and in (4) WKY (WKY-H) rats. (5) Endogenous homocyst(e)ine levels were reduced slightly but not significantly from 18.1 +/- 0.5 microM to 12.5 +/- 0.7 microM in SHR by folic acid administration (SHR-F). Plasma and tissue levels of homocyst(e)ine were determined by HPLC and spectrophotometric methods. Plasma and sympathetic ganglion (neuronal) matrix metalloproteinase (MMP) activity was measured by zymography. Activity of neuronal MMP was increased in hyperhomocyst(e)inemic rats as compared with controls. Mean arterial pressure (mmHg) was 95 +/- 5, 126 +/- 8,157 +/- 10, 188 +/- 5, and 165 +/- 12 in WKY, WKY-H, SHR, SHR-H, and SHR-F, respectively. Urinary protein (mg/day) was 0.11 +/- 0.03, 0.88 +/- 0.22, 0.47 +/- 0.10, 0.89 +/- 0.21, and 0.81 +/- 0.21 in WKY, WKY-H. SHR, SHR-H, and SHR-F, respectively, as measured by the Bio-Rad dye binding assay. The relationships between increased arterial pressure, plasma homocyst(e)ine, and urinary protein were delineated. Plasma and neuronal creatinine phosphokinase (CK) isoenzymes were measured by agarose gel electrophoresis. All three CK isoenzymes, i.e., MM, MB, and BB, specific for skeletal, cardiac, and nerve tissue, respectively, were induced following 12 weeks' hyperhomocyst(e)inemia, suggesting multiorgan injury by homocyst(e)ine. Homocyst(e)ine induces endocardial endothelial cell (capillary) apoptosis and may reduce capillary cell density. Structural damage to aorta, myocardium, kidney, and renalureter was analyzed by histology. Results suggested an integrated physiological role of homocyst(e)ine in injury to the endothelial/epithelial cell lining in the respective organs.
Ti t l e A fa mily-c a r e r u b ri c : d ev elo pi n g fa mily c a r e a n d c o m m u ni c a tio n s kills u si n g si m ul a tio n
In many remodeling tissues, such as the heart, collagen degradation to provide new integrin-binding sites is required for survival. However, complete loss of integrin signaling due to disconnection from extracellular matrix (ECM) leads to apoptosis and dilatation. To test the hypothesis that a mutation in type I collagen gene induces cardiomyopathy, we employed a metalloproteinase-resistant collagen mutant homozygous transgenic male (B6,129-Colla-1) and compared with age-sex matched wildtype C57BL/J6 control mice. At the age of 38-42 weeks, aortic and left ventricle (LV) pressure were measured. The LV wall thickness and diameter were measured by a digital micrometer. The levels of matrix metalloproteinase-2 (MMP-2) activity and cardiospecific tissue inhibitor of metalloproteinase-4 (TIMP-4) were measured by zymography and Western blot analyses, respectively. The levels of collagenolysis were measured by Western blot using anti-collagen antibody. In transgenic and wildtype mice, end-diastolic pressure (EDP) was 8.3 +/- 1.7 and 6.5 +/- 1.1 mmHg; LV diameter was 3.43 +/- 0.07 and 2.94 +/- 0.05 mm; wall thickness was 1.18 +/- 0.03 and 1.28 +/- 0.04 mm; end-diastolic wall stress was 600 +/- 158 and 347 +/- 49 dynes/cm(2), respectively. The increase in LV wall stress was associated with increased MMP-2 activity, increased collagenolysis, and decreased levels of TIMP-4. This leads to reduced elastic compliance in collagen mutant transgenic mice. The occurrence of cardiomyopathy in adult Colla-1 mice may be a significant confounding factor as it may be indicative of increased basal levels of ECM disruption. This phenotype is what would be expected if collagen degradation normally supplies integrin ligands during cardiac muscle remodeling.
The unconventional nature of the Global War on Terror necessitates an immediate and substantial increase in the manning of U.S. Special Operations. To this end, the Navy Sea, Air, Land (SEAL) community is faced with the challenge of graduating more Special Operations personnel without sacrificing the high intensity of training. These circumstances have led to a renaissance of interest in identifying, recruiting, selecting, and retaining individuals who are best equipped to succeed in a military environment known to test every dimension of a candidate's will. As the first of a two-part series, the purposes of this paper were to (1) review the currently available literature addressing factors and characteristics that may predict the performance and success of Basic Underwater Demolition/SEAL (BUD/S) candidates, (2) identify critical paths for future research, focusing on that which may yield the highest operational return in the shortest time. Thirteen studies were critically reviewed, and future research directions were discussed.
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