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Describes the Premedical Honors College (PHC), an eight-year, BS-MD program created by Baylor College of Medicine and the University of Texas-Pan American to increase the number of physicians addressing underserved populations in Texas. An outcomes study comparing PHC matriculants with students of similar academic ability, ethnicity, and interest in medicine revealed that the odds of medical school matriculation were seven times higher for PHC students than for non-PHC students. (EV)

We studied cardiac function in young and old, wild-type (WT), and longer-living Little mice using cardiac flow velocities, echocardiographic measurements, and left ventricular (LV) pressure (P) to determine if enhanced reserves were in part responsible for longevity in these mice. Resting/baseline cardiac function, as measured by velocities, LV dimensions, +dP/[dt.sub.max], and -dP/[dt.sub.max], was significantly lower in young Little mice versus young WT mice. Fractional shortening (FS) increased significantly, and neither +dP/[dt.sub.max] nor -dP/[dt.sub.max] declined with age in Little mice. In contrast, old WT mice had no change in FS but had significantly lower +dP/ [dt.sub.max] and -dP/[dt.sub.max] versus young WT mice. Significant decreases were observed in the velocity indices of old Little mice versus old WT mice, but other parameters were unchanged. The magnitude of dobutamine stress response remained unchanged with age in Little mice, while that in WT mice decreased. These data suggest that while resting cardiac function in Little mice versus WT mice is lower at young age, it is relatively unaltered with aging. Additionally, cardiac function in response to stress was maintained with age in Little mice but not in their WT counterparts. Thus, some mouse models of increased longevity may not be associated with enhanced reserves.

Epidemiological studies indicate that obesity, insulin resistance, and diabetes are important comorbidities of patients with ischemic heart disease and increase mortality and development of congestive heart failure after myocardial infarction. Although ob/ob and db/db mice are commonly used to study obesity with insulin resistance or diabetes, mutations in the leptin gene or its receptor are rarely the cause of obesity in humans, which is, instead, primarily a consequence of dietary and lifestyle factors. Therefore, we used a murine model of diet-induced obesity to examine the physiological effects of obesity and the inflammatory and healing response of diet-induced obese (DIO) mice after myocardial ischemia-reperfusion injury. DIO mice developed hyperinsulinemia and insulin resistance and hepatic steatosis, with significant ectopic lipid deposition in the heart and cardiac hypertrophy in the absence of significant changes in blood pressure. The mRNA levels of chemokines at 24 h and cytokines at 24 and 72 h of reperfusion were higher in DIO than in lean mice. In granulation tissue at 72 h of reperfusion, macrophage density was significantly increased, whereas neutrophil density was reduced, in DIO mice compared with lean mice. At 7 days of reperfusion, collagen deposition in the scar was significantly reduced and left ventricular (LV) dilation and cardiac hypertrophy were increased, indicative of adverse LV remodeling, in infarcted DIO mice. Characterization of a murine diet-induced model of obesity and insulin resistance that satisfies many aspects commonly observed in human obesity allows detailed examination of the adverse cardiovascular effects of diet-induced obesity at the molecular level. insulin resistance; cardiac lipotoxicity; ischemia-reperfusion injury; left ventricular remodeling

We have developed a high-frequency, high-resolution Doppler spectrum analyzer (DSPW) and compared its performance against an adapted clinical Medasonics spectrum analyzer (MSA) and a zero-crossing interval histogram (ZCIH) used previously by us to evaluate cardiovascular physiology in mice. The aortic velocity (means [+ or -] SE: 92.7 [+ or -] 2.5 versus 82.2 [+ or -] 1.8 cm/s) and aortic acceleration (8194 [+ or -] 319 versus 5178 [+ or -] 191 cm/[s.sup.2]) determined by the DSPW were significantly higher compared to those by the MSA. Aortic ejection time was shorter (48.3 [+ or -] 0.9 versus 64.6 [+ or -] 1.8 ms) and the isovolumic relaxation was longer (17.6 [+ or -] 0.6 versus 13.5 [+ or -] 0.6 ms) when determined by the DSPW because it generates shorter temporal widths in the velocity spectra when compared to the MSA. These data indicate that the performance of the DSPW in evaluating cardiovascular physiology was better than that of the MSA. There were no significant differences between the aortic pulse wave velocity determined by using the ZCIH (391 [+ or -] 16 cm/s) and the DSPW (394 [+ or -] 20 cm/s). Besides monitoring cardiac function, we have used the DSPW for studying peripheral vascular physiology in normal, transgenic, and surgical models of mice. Several applications such as the detection of high stenotic jet velocities (>4 m/s), vortex shedding frequencies (250 Hz), and subtle changes in wave shapes in peripheral vessels which could not obtained with clinical Doppler systems are now made possible with the DSPW. Index Terms--High-frequency pulsed Doppler ultrasound, mouse cardiac function, mouse cardiovascular physiology, pulse-wave velocity, stenotic jet velocities, vortex shedding frequencies.

Limitation of damage after ischemia and reperfusion injury to the myocardium remains an elusive clinical goal. Previous studies have suggested that molecular chaperones, which include members of the heat shock protein (Hsp) family, may have cardioprotective effects, although the protective role of endogenous chaperones has not been well documented. CHIP (carboxyl terminus of Hsp70-interacting protein) is a cochaperone/ubiquitin ligase that integrates the response to stress at multiple levels. We tested the response of CHIP(-/-) mice to in vivo ischemia and reperfusion injury induced by left anterior descending coronary artery ligation. Compared with wild-type littermates, CHIP(-/-) mice had decreased survival and increased incidence of arrhythmias during reperfusion. The size of myocardial infarction, as assessed by the ratio of infarct area to area at risk, was 50% greater in CHIP(-/-) mice. Increased infarct size was accompanied by impaired upregulation of the chaperone Hsp70 after ischemia-reperfusion injury. In situ analysis also indicated that hearts of CHIP(-/-) mice were more prone to develop apoptosis in cardiomyocytes and especially endothelial cells of intramural vessels. Previous studies have found that CHIP plays a central role in maintaining protein quality control and coordinating the response to stress. The present data indicate that these functions of CHIP provide a critical cardioprotective effect in the setting of ischemia-reperfusion injury due in part to increased apoptosis in cardiac cells. Quality control mechanisms therefore may be underappreciated clinical targets for maximizing myocardial protection after injury. chaperone; heat shock protein; apoptosis

Despite the extensive use of genetically altered mice to study cardiovascular physiology and pathology, it remains difficult to quantify arterial function noninvasively in vivo. We have developed a noninvasive Doppler method for quantifying vessel wall motion in anesthetized mice. A 20-MHz probe was held by an alligator clip and positioned over the carotid arteries of 16 mice, including six 3- to 5-mo-old wild-type (WT), four 30-mo-old senescent (old), two apolipoprotein E null (ApoE), and four [alpha]-smooth muscle actin null ([alpha]-SMA) mice. Doppler signals were obtained simultaneously from both vessel walls and from blood flow. The calculated displacement signals from the near and far walls were subtracted to generate a diameter signal from which the excursion and an augmentation index were calculated. The excursion ranged between 13 [micro]m (in ApoE) and 95 [micro]m (in [alpha]-SMA). The augmentation index was lowest in the WT mice (0.06) and highest in the old mice (0.29). We conclude that Doppler signal processing may be used to measure vessel wall motion in mice with high spatial and temporal resolution and that diameter signals can replace pressure signals for calculating the augmentation index. This noninvasive method is able to identify and confirm characteristic changes in arterial properties previously associated with age, atherosclerosis, and the absence of vascular tone. Doppler displacement; arterial mechanics; blood velocity; carotid artery

The placement of a ligature to constrict the transverse aorta has become a standard procedure to induce cardiac hypertrophy in mice. Apart from cardiac response, there are adaptive changes in the proximal and distal arterial system that function to maintain adequate peripheral perfusion. The purpose of this study was to characterize the peripheral vascular response by measuring the carotid blood flow using noninvasive Doppler methods, and to investigate the effect of aging on the adequacy and timing of the response after aortic banding in mice. Five 16-month-old and 9 4-month-old male B6D2F1 mice underwent transverse aortic banding. Blood flow velocity was measured with Doppler in the right and left carotid arteries (RCA and LCA) before, 1 day after, and 7 days after, banding. Pulsatility index defined as (peak--minimum)/mean velocity was used to estimate local compliance and distal arterial resistance. The RCA/LCA mean velocity ratio was lower and pulsatility index ratio was higher at 1 day after banding in older mice. However, at 7 days, the RCA/LCA mean velocity ratio and pulsatility index ratio were similar between the 2 age groups. Our data indicate that there is an age-related delay in the development of vascular adaptations in carotid arteries after aortic banding. Older mice take a longer time for adaptation to establish adequate and equal mean flow velocity in the carotid arteries.

Mice are used with increasing frequency as models of human cardiovascular diseases, but significant gaps exist in our knowledge of vascular function in the aging mouse. We determined aortic input impedance spectra, pulse wave velocity, and augmentation index in adult (8-mo-old) and old (29-mo-old) mice to determine whether arterial stiffening occurred with age in mice as it does in humans. Pressure and blood velocity signals measured simultaneously from the same location in the ascending aorta were used to determine input impedance spectra (0-10 harmonics). The first minimum of the impedance modulus occurred at the second harmonic in adult mice but shifted to the fourth harmonic in old mice. Characteristic impedance (average of 2nd-10th harmonic) was 57% higher in old mice: 471 [+ or -] 62 vs. 299 [+ or -] 10 (SE) dyn.s.[cm.sup.-3] (P < 0.05). Pulse pressure and augmentation index, determined from the aortic pressure signals, were also higher in old mice: 42 [+ or -] 2.2 vs. 29 [+ or -] 4.9 mmHg (P < 0.05) and 37 [+ or -] 5 vs. 14 [+ or -] 2% (P < 0.005). Aortic pulse wave velocity measured from the timing of upstrokes of the Doppler velocity signals was 45% higher in old mice: 416 [+ or -] 22 vs. 286 [+ or -] 14 cm/s (n = 3, P < 0.01). These results reproduce age-related findings reported in humans and confirm that mice may be used as models of age-related vascular stiffening. aging mouse; arterial stiffness; characteristic impedance; pulse wave velocity; augmentation index

Myocardial infarction is associated with the rapid induction of mononuclear cell chemoattractants that promote monocyte infiltration into the injured area. Monocyte-to-macrophage differentiation and macrophage proliferation allow a long survival of monocytic cells, critical for effective healing of the infarct. In a canine infarction-reperfusion model, newly recruited myeloid leukocytes were markedly augmented during early reperfusion (5-72 h). By 7 days, the number of newly recruited myeloid cells was reduced, and the majority of the inflammatory cells remaining in the infarct were mature macrophages. Macrophage colony-stimulating factor (MCSF) is known to facilitate monocyte survival, monocyte-to-macrophage conversion, and macrophage proliferation. We demonstrated marked induction of MCSF mRNA in ischemic segments persisting for at ]east 5 days after reperfusion. MCSF expression was predominantly localized to mature macrophages infiltrating the infarcted myocardium; the expression of the MCSF receptor, c-Fms, a protein with tyrosine kinase activity, was found in these macrophages but was also observed in a subset of microvessels within the infarct. Many infarct macrophages expressed proliferating cell nuclear antigen, a marker of proliferative activity. In vitro MCSF induced monocyte chemoattractant protein-1 synthesis in canine venous endothelial cells. MCSF-induced endothelial monocyte chemoattractant protein-1 upregulation was inhibited by herbimycin A, a tyrosine kinase inhibitor, and by LY-294002, a phosphatidyl-inositol 3'-kinase inhibitor. We suggest that upregulation of MCSF in the infarcted myocardium may have an active role in healing not only through its effects on cells of monocyte/ macrophage lineage, but also by regulating endothelial cell chemokine expression. inflammation; reperfusion; chemokine; growth factors; macrophage colony-stimulating factor

Hypertrophic growth is a risk factor for mortality in heart diseases. Mechanisms are lacking for this global increase in RNA and protein per cell, which underlies hypertrophy. Hypertrophic signals cause phosphorylation of the RNA polymerase II C-terminal domain, required for transcript elongation. RNA polymerase II kinases include cyclin-dependent kinases-7 (Cdk7) and Cdk9, components of two basal transcription factors. We report activation of Cdk7 and -9 in hypertrophy triggered by signaling proteins (G[alpha]q, calcineurin) or chronic mechanical stress. Only Cdk9 was activated by acute load or, in culture, by endothelin. A preferential role for Cdk9 was shown in RNA polymerase II phosphorylation and growth induced by endothelin, using pharmacological and dominant-negative inhibitors. All four hypertrophic signals dissociated 7SK small nuclear RNA, an endogenous inhibitor, from cyclin T-Cdk9. Cdk9 was limiting for cardiac growth, shown by suppressing its inhibitor (7SK) in culture and preventing downregulation of its activator (cyclin T1) in mouse myocardium. Note:: In the AOP version of this article, the numbering of the author affiliations was incorrect. This has now been fixed, and the affiliations appear correctly online and in print., Author(s): Motoaki Sano [1, 3]; Maha Abdellatif [6]; Hidemasa Oh [1, 3]; Min Xie [1, 3]; Luigi Bagella [7]; Antonio Giordano [7]; Lloyd H. Michael [2, 3]; Francesco J. DeMayo [...]

Entman. Heart failure and greater infarct expansion in middle-aged mice: a relevant model for postinfarction failure. Am J Physiol Heart Circ Physiol 282: H615-H621, 2002; 10.1152/ajpheart.00206.2001.--Young mice tolerate myocardial loss after coronary artery ligation (CAL) without congestive heart failure (CHF) signs or mortality. We predicted a CHF phenotype after CAL in aged mice. Left coronary artery ligation produced permanent myocardial infarcts (MI). Mortality was higher in male 14-mo-old C57BL/6N mice (Older mice) than in 2-mo-old mice (Young mice) (16 of 25 Older mice died vs. 0 of 10 Young mice, P < 0.02). After 8 wk, rales, weight loss, and lethargy preceded deaths. Captopril (50 mg * [kg.sup.-1] * [day.sup.-1]) increased Older mouse survival (6 of 22 died, P < 0.02). Captopril improved systolic function (peak aortic blood velocity) from 76 [+ or -] 6% of baseline in untreated Older mice to 93 [+ or -] 8% (P < 0.036). At 24 h, MI comprised 28 [+ or -] 4% of the left ventricle in Young mice, surprisingly larger than that in Older mice (18 [+ or -] 2%, P < 0.011). Endocardial area underlying the infarct scar was significantly larger in Older mice than in Young mice. Captopril did not reduce expansion but markedly reduced septal hypertrophy. Aging reduces compensatory ability in mice despite smaller acute infarcts. Less effective myocardial repair, greater infarct expansion, and septal hypertrophy are seen with aging. Aging is a more relevant murine model of post-MI heart failure in patients. heart failure; myocardial infarction; aging; mouse

Nossuli, Tareck O., Nikolaos G. Frangogiannis, Pascal Knuefermann, Venkatesh Lakshminarayanan, Oliver Dewald, Alida J. Evans, Jacques Peschon, Douglas L. Mann, Lloyd H. Michael, and Mark L. Entman. Brief murine myocardial I/R induces chemokines in a TNF[alpha]-independent manner: role of oxygen radicals. Am J Physiol Heart Circ Physiol 281: H2549-H2558, 2001.--Early chemokine induction in the area at risk of an ischemic-reperfused (I/R) myocardium is first seen in the venular endothelium. Reperfusion is associated with several induction mechanisms including increased extracellular tumor necrosis factor (TNF)-[alpha], reactive oxygen intermediate (ROI) species formation, and adhesion of leukocytes to the venular endothelium. To test the hypothesis that chemokine induction in cardiac venules can occur by ROIs in a TNF-[alpha]-independent manner, and in the absence of leukocyte accumulation, we utilized wild-type (WT) and TNF-[alpha] double-receptor knockout mice (DKO) in a closed-chest mouse model of myocardial ischemia (15 rain) and reperfusion (3 h), in which there is no infarction. We demonstrate that a single brief period of I/R induces significant upregulation of the chemokines macrophage inflammatory protein (MIP) -1[alpha], -1[beta], and -2 at both the mRNA and protein levels. This induction was independent of TNF-[alpha], whereas levels of these chemokines were increased in both WT and DKO mice. Chemokine induction was seen predominantly in the endothelium of small veins and was accompanied by nuclear translocation of nuclear factor-[kappa]B and c-Jun (AP-l) in venular endothelium. Intravenous infusion of the oxygen radical scavenger N-2-mercaptopropionyl glycine (MPG) initiated 15 min before ischemia and maintained throughout reperfusion obviated chemokine induction, but MPG administration after reperfusion had begun had no effect. The results suggest that ROI generation in the reperfused myocardium rapidly induces C-C and C-X-C chemokines in the venular endothelium in the absence of infarction or irreversible cellular injury. macrophage inflammatory protein; endothelium; transgenic animals Received 9 February 2001; accepted in final form 22 August 2001

The transforming-growth-factor-[beta]-activated kinase TAK1 is a member of the mitogen-activated protein kinase kinase kinase family, which couples extracellular stimuli to gene transcription. The in vivo function of TAK1 is not understood. Here, we investigated the potential involvement of TAK1 in cardiac hypertrophy. In adult mouse myocardium, TAK1 kinase activity was upregulated 7 days after aortic banding, a mechanical load that induces hypertrophy and expression of transforming growth factor [beta]. An activating mutation of TAK1 expressed in myocardium of transgenic mice was sufficient to produce p38 mitogen-activated protein kinase phosphorylation in vivo , cardiac hypertrophy, interstitial fibrosis, severe myocardial dysfunction, &apos;fetal&apos; gene induction, apoptosis and early lethality. Thus, TAK1 activity is induced as a delayed response to mechanical stress, and can suffice to elicit myocardial hypertrophy and fulminant heart failure., Author(s): Dou Zhang [1, 2, 3]; Vinciane Gaussin [1, 3]; George E. Taffet [2, 3]; Narasimhaswamy S. Belaguli [4]; Miho Yamada [4]; Robert J. Schwartz [2, 4]; Lloyd H. Michael [...]

Two hours of occlusion followed by reperfusion or permanent left anterior descending coronary artery occlusion in C57BL/6 mice were examined for anatomic and functional changes. About 30% of the left ventricle had infarcts generated by both interventions measured at 24 h and equivalent suppression of LV ejection velocity and filling velocity measured by Doppler ultrasound at 1 wk. The results showed that later reperfusion appeared to reduce the degree of infarct expansion.

Researchers have investigated whether noninvasive Doppler velocimetry using high-speed signal processing can provide signals from which aortic pulse-wave velocity (PWV) can be determined in mice. This involved using a custom-made 20-MHz pulsed Doppler instrument to obtain blood flow velocity signals from the aortic arch and the abdominal aorta. It was found that arterial tonometry using micromanometers can be used to obtain details of high-fidelity pressure waveforms from mice without arterial cannulation.

The noninvasive pulsed Doppler ultrasound measurements of cardiac systolic and diastolic function in mice give results similar to those of larger species with respect to magnitude and response to hyperthyroidism and aging. The induction of hyperthyroidism results in an increase in systolic and diastolic function in mouse. Diastolic function is accompanied by ATP-dependent Ca2+ ion uptake. The sequestration of calcium ions to sarcoplasmic reticulum controls the cardiac relaxation.

Genetically altered mice and unique experimental procedures involving coronary occlusion were developed for the study of the inflammatory reactions following myocardial ischemia-reperfusion. The procedures allow the assessment of cardiac function, area at risk and infarct size. These procedures combined with transgenic mice overexpressing or deficient in certain genes would allow the assessment of the role of specific gene products in the pathophysiology of inflammation and myocardial injury following ischemia-reperfusion.

Audio-Doppler signal recording from the ascending aorta of mice using a 20-MHz transducer helps assess the utility of 20-MHz pulsed Doppler ultrasound in monitoring cardiovascular parameters in small animals. Playback of the audio signals into a fast Fourier transform analyzer helps measure ejection time, heart rate, mean and peak velocities, stroke distance, rise time and acceleration from the spectral envelopes. Aortic velocity signals are obtained through moistened fur using the transducer, indicating that 20-MHz ultrasound can be successfully applied for the noninvasive measurement of aortic velocity in small animals.

Adult and neonatal cardiac sarcolemmal preparations from dogs were used in the determination of postnatal developmental changes in transporter function and density. Results reveal that the density of sodium-potassium pumpschanges with age. In contrast, the sodium-calcium exchanger does not exhibit age-related alterations. This implies that calcium absorption through the sodium-calcium exchanger is more significant in neonates than in adults.