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Biomedical subjects

M A McDonnell

Publications and source records attributed to M A McDonnell.

13 recordsLinked to original sources
PubMed2006

Autophagy delays apoptotic death in breast cancer cells following DNA damage.

Early signaling in camptothecin-treated MCF-7 cells followed an intrinsic pathway, but death was delayed and late events exhibited few hallmarks of apoptosis. BH3-only proteins, such as Noxa, Puma and BimEL, were activated and localized to mitochondrial sites within 24 h following drug exposure. However, caspase activity was low and death was unaffected by caspase inhibition. Transmission electron micrographs showed the presence of large vacuoles in drug-treated cells. An autophagic survival response has been attributed to MCF-7 cells following nutrient starvation or exposure to tamoxifen. Here, we show that autophagy also plays an important role in the delayed DNA damage response. Confocal microscopy revealed colocalization of mitochondria with large autophagic vacuoles and inhibitors of autophagy increased mitochondrial depolarization and caspase-9 activity, and accelerated cell death. Furthermore, downregulation of autophagy proteins, Beclin 1 and Atg7, unmasked a caspase-dependent, apoptotic response to DNA damage. We propose that a post-mitochondrial caspase cascade is delayed as a result of early disposal of damaged mitochondria within autophagosomes. Our data also suggest that the use of autophagy as a means of delaying apoptosis or prolonging survival may be characteristic of noninvasive breast tumor cells. These studies underscore a potential role for autophagy inhibitors in combination with conventional chemotherapeutic drugs in early breast cancer therapy.

Apoptosis↗
PubMed2003

Caspase-9 is activated in a cytochrome c-independent manner early during TNFalpha-induced apoptosis in murine cells.

FL5.12 pro-B lymphoma cells utilize the mitochondrial pathway to apoptosis in response to tumor necrosis factor (TNF) receptor occupation, yet high levels of the Bcl-2 family antiapoptotic protein, Bcl-x(L), fail to protect these cells against TNF-receptor-activated death. Bcl-x(L) expression delays, but does not totally block, the release of mitochondrial cytochrome c (cyt c) in these cells in response to TNFalpha-induced apoptosis and caspase-9 is processed prior to mitochondrial cyt c release under these circumstances. Early processing of caspase-9 also occurred in Apaf-1 knockout murine fibroblasts in response to TNF-receptor occupation. A caspase-9-specific inhibitor was more effective in delaying the progression of apoptosis in the FL5.12 Bcl-x(L) cells than was an inhibitor specific to caspase-3. Furthermore, downregulation of caspase-9 levels by RNA interference resulted in partial protection of these cells against TNF-receptor-activated apoptosis, indicating that caspase-9 activation contributed to early amplification of the caspase cascade. Consistent with this, proteolytic processing of caspase-9 was observed prior to processing by caspase-3, suggesting that caspase-3 was not responsible for early caspase-9 activation. We show that murine caspase-9 is efficiently processed by active caspase-8 at SEPD, the motif at which caspase-9 autoprocesses following its recruitment to the apoptosome. Our results suggest that, in addition to processing procaspase-3 and the BH3 protein Bid, active caspase-8 can cleave and activate procaspase-9 in response to TNF receptor crosslinking in murine cells.

Amino Acid Sequence↗
PubMed2001

Antagonistic effects of TGFbeta1 and BMP-6 on skin keratinocyte differentiation.

Several members of the transforming growth factor beta (TGFbeta) superfamily are expressed in the developing murine epidermis. Among these are TGFbeta1, which is found in the basal layer, and bone morphogenetic protein (BMP)-6, located in the suprabasal layers. Although the role of TGFbeta in cell growth has been studied extensively, little is known about the effects of these factors on keratinocyte differentiation. This study demonstrates that BMP-6 acts to positively regulate the differentiation of primary skin keratinocytes grown in culture. In contrast, TGFbeta1 antagonizes keratinocyte differentiation blocking the upregulation of keratin markers by BMP-6. We show that the effects of BMP-6 on expression of keratin 1 (K1), a marker of differentiation, requires signaling through the Smad pathway. In addition, regulation of K1 levels by BMP-6 is modulated by the SEK signaling pathway. This suggests that regulation of keratinocyte differentiation by BMP-6 involves multiple signaling systems.

Adenoviridae↗
PubMed1999

Interdependent SMAD and JNK signaling in transforming growth factor-beta-mediated transcription.

SMAD and JNK cascades are essential components of the transforming growth factor-beta (TGF-beta) signaling machinery and are implicated in common transcriptional responses. However, the relationship of these pathways to one another downstream of the TGF-beta receptor complex is unknown. We show that JNK is rapidly activated by TGF-beta in a SMAD-independent manner and phosphorylates Smad3 outside its -SSXS motif. Smad3 phosphorylation by JNK facilitates both its activation by the TGF-beta receptor complex and its nuclear accumulation. JNK regulates SMAD- and TGF-beta-mediated transcriptional responses, yet JNK activators only partially stimulate transcriptional responses characteristic of TGF-beta without coincident SMAD pathway activation. These results suggest an interdependent relationship between the JNK and SMAD pathways in TGF-beta-mediated transcription.

Cells, Cultured↗
PubMed1983

Recognition and diagnosis of apical hypertrophic cardiomyopathy.

Recognition and diagnosis of nonobstructive apical hypertrophic cardiomyopathy is important to begin to understand the natural history and prognosis of such patients. Our experience with three patients indicates that a clue to the recognition of apical hypertrophic cardiomyopathy lies in the striking electrocardiographic repolarization changes consistent with subendocardial ischemia often prompting admission to the coronary care unit. The diagnosis of apical hypertrophic cardiomyopathy in two patients was confirmed by two-dimensional echocardiographic apical views, but due to a technically inadequate echocardiogram, the diagnosis in the third patient was made by left ventriculography. Two of the three patients underwent right and left cardiac catheterization and their rest and exercise hemodynamic data were consistent with restrictive cardiomyopathy.

Cardiomyopathy, Hypertrophic↗
PubMed1981

Dependence of ventricular fibrillation propensity on coronary blood flow without myocardial ischemia.

Ventricular fibrillation threshold (VFT) changes have been linked to coronary blood flow (CBF) in the context of CBF reduction and subsequent myocardial hypoxia. To clarify the effect of CBF on VFT in the absence of myocardial hypoxia, 18 open-chest pentobarbital-anesthetized dogs with uniformly controlled heart rate, cardiac output, and mean systemic arterial pressure (SAP) were studied as follows: CBF, coronary sinus O2 content (CcsO2), and thereby myocardial O2 consumption were continuously monitored. Baseline VFT determined by the single stimulus scanning technique was 33.0 +/- 3.9 mA. Initial values of CBF index (I) and VFT (n = 18) were positively correlated (VFTmA = 0.8 +/- 0.245 . CBFI ml/min . 100g-1LV; r = 0.60, p less than 0.01). Stepwise CBFI increments up to five times in excess of initial 131.5 +/- 9.7 ml/min . 100g-1LV were then induced by changing in random order. SAP (n = 10), left coronary perfusion pressure (n = 7), and arterial O2 content (n = 10) with VFT determined at each step; CcsO2 remained above 5.5 vol% while CBFI and VFT changes were positively correlated, and mean weighted slope of VFTmA = 16.6 +/- 0.103 . CBFI ml/min . 100 g-1Lv (r = 0.82, p less than 0.05). Systemic or coronary perfusion pressure and arterial or coronary sinus O2 content did not appear to affect VFT independently. It is concluded that even in the absence of myocardial hypoxia, CBF itself is a major determinant of VFT and thereby of innate arrhythmogenic propensity.

Animals↗
PubMed1981

Absence of clinical pulmonary edema despite elevated wedge pressures.

Pulmonary hemodynamic data were collected for 116 patients with a resting mean pulmonary artery wedge pressure of 25 mm Hg or greater who underwent exercise during cardiac catheterization without showing acute pulmonary edema. While the mechanism for the absence of evidence of pulmonary edema with pulmonary artery wedge pressure in excess of plasma oncotic pressure is unclear, presumably, it relates to compensatory changes in the structure and function of the pulmonary capillaries, alveolar wall, and lymphatic drainage capacity.

Adult↗
PubMed1979

Comparative effect of counterpulsation and bypass on left ventricular myocardial oxygen consumption and dynamics before and after coronary occlusion.

In this preparation counterpulsation effect was found equivalent to 42 +/- 7% of complete left ventricular bypass before, and 46 +/- 9% post-coronary occlusion. We conclude that counterpulsation is effective mainly by reducing a major determinant of myocardial oxygen consumption, i.e., afterload, whereas left ventricular bypass by reducing primarily preload results in secondary afterload reduction when peripheral resistance is unchanged. At the higher left ventricular bypass levels, reduction of myocardial oxygen consumption is far greater than during balloon counterpulsation. Acute functional loss of myocardium does not alter the effect of these assist methods regarding the reduction of myocardial oxygen consumption. Whether selection of either method for clinical application should be made only on the basis of its capability for reduction of myocardial oxygen consumption remains to be justified by conclusive demonstration of beneficial effect of reduction of myocardial oxygen consumption in the specific circulatory disorders.

Animals↗
PubMed1978

Intermittent severe mitral regurgitation.

The findings in two patients with hemodynamic evidence of intermittent severe mitral regurgitation with cyclic variation in right and left ventricular pressures are presented. Both patients had aortic and mitral valvular regurgitation of unknown etiology without definite evidence of papillary muscle dysfunction. The basis for the variation in the degree of mitral regurgitation is unclear.

Aortic Valve Insufficiency↗
PubMed1975

Comparison of clinical and hemodynamic assessment of cardiac disability.

Clinical versus hemodynamic assessment of cardiac disability was compared in 187 patients with either coronary artery or valvular disease classified using the New York Heart Association classification (excluding class IV). The following variables were analyzed during rest and exercise: arteriovenous oxygen content difference (CavO2), cardiac index (CI), pulmonary artery pressure (PAP), pulmonary artery wedge pressure (PAWP), pulmonary arteriolar resistance index (PARI) and heart rate (HR). 180 comparisons of variables were made. Hemodynamic evaluation paralleled clinical evaluation only 19 times during rest and 12 during exercise. There were 5 instances of clinical and hemodynamic distinction between class I and II, 14 between class I and III and 12 between class II and III. Correlation was best in mitral stenosis. The most useful variable was CI followed by PAP and CavO2. HR was not helpful. This study emphasizes that subjective clinical disability may not correlate with physiologic derangement in certain patients.

Adolescent↗