Atherosclerotic plaque color can be consistently measured during angioscopy with quantitative colorimetry. High yellow color intensity, determined by this system, was associated with LCTCs. Quantitative colorimetry during angioscopy may be used for detection of LCTCs, which may be markers of vulnerability.

Cardiovascular disease is the leading cause of mortality for both men and women in developed countries. The sex steroid hormone estrogen is required for normal vascular physiology. Estrogen functions by binding to intracellular estrogen receptors (ER), ERalpha and ERbeta, ligand-activated transcription factors that are expressed in both vascular endothelial and smooth muscle cells. We recently demonstrated that long-term (8 d) estrogen treatment in vivo in mice recruits distinct vascular gene sets mediated by ERalpha and ERbeta and that the promoters from these gene sets are enriched for binding sites of specific transcription factors, leading to the hypothesis that estrogen initiates a cascade of early transcriptional events that modulate gene expression in the vasculature. Here we test this hypothesis using gene expression profiling to examine initial transcriptional events (2-8 h) mediated by estrogen in blood vessels. Our data reveal that 1) estrogen regulates temporally distinct cascades of vascular gene expression, 2) initially, estrogen-mediated vascular gene repression predominates, 3) the earliest estrogen-recruited gene program is enriched in vascular transcription factors that can interact with binding sites present in estrogen-regulated vascular genes recruited subsequently, and 4) estrogen-regulated genes recruited next have specific functions, including lipid metabolism and cellular growth and proliferation that are potentially important for estrogen's known vascular functions. In summary, estrogen directly and rapidly recruits specific transcriptional factors that then propagate distinct cascades of gene expression. These data define the temporal recruitment of specific vascular genes by estrogen and enable further analysis of the mechanisms by which estrogen directly regulates vascular function.

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This human-to-porcine coronary xenograft model allows intravascular imaging of human coronary pathology under conditions of blood flow and motion, and may be used to develop technologies aimed at identifying high-risk plaques.

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Protein Kinase G I (PKGI) has been implicated as a negative regulator of pathologic cardiac hypertrophy [1,2], though the specific molecular mechanisms involved are unknown. To test the hypothesis that PKGIα negatively regulates cardiac hypertrophy, we characterized the cardiac phenotype in mice homozygous for a leucine zipper mutant (LZM) form of PKGIα in which critical amino acids in the N-terminal LZ motif have been substituted to disrupt PKGIα LZ binding to specific downstream effector proteins. We characterized the hearts of these LZM mice morphologically, by echocardiography and invasive hemodynamics in the unstressed state, and following pressure overload-induced cardiac hypertrophy. In the unstressed state, male PKG Iα LZM mice develop progressive left ventricular hypertrophy (LV mass/ tibia length) compared with wild type (WT) littermates with LV mass 12.3% greater at 30 weeks of age (p = 0.05, n = 10 WT, 9 LZM); and 27% greater at 60 weeks of age (p < 0.001, n = 5 WT, 13 LZM). Compared with age matched WT mice, the hearts of 30 week old PKGIα mutants are hypercontractile with decreased end systolic diameter (2.25 mm WT vs 1.95 mm LZM, p = 0.02) and increased fractional shortening (36.9% WT vs 42.2% LZM, p = 0.03) on echocardiography (n = 9 wt, 9 LZM). Invasive hemodynamic assessment demonstrates that LZM mice also have increased left ventricular systolic pressure (107.0 mmHg WT vs 120.7 mmHg LZM, p = 0.04), developed pressure (107.5 mmHg WT vs 119.2 mmHg LZM, p = 0.05), and LV dP/dt max (8972 mmHg/s WT vs 9802 mmHg/s LZM, p = 0.13).To evaluate the response to hemodynamic stress, cardiac hypertrophy was induced by transaortic constriction (TAC) in 10-12 week old male WT (n = 21) and LZM (n = 15) mice. TAC resulted in striking and early mortality in the LZM mice (60%) compared to the WT (19%) mice at 21 days post procedure (p = 0.008), with evidence of accelerated LV hypertrophy in the mice that died early (LV mass/tibia length 9.8 mg/mm in the early LZM deaths vs 7.2 mg/mm in WT 21 day survivors, p < 0.001). Additionally, the LZM early deaths had evidence of congestive heart failure with increased right ventricular mass (RV mass/ tibia length 1.8 mg/mm in LZM early deaths vs 1.2 mg/mm in WT 21 day survivors, p < 0.05), and increased lung mass (23.1 mg/mm LZM early deaths vs 12.5 mg/ mm in WT 21 day survivors, p < 0.005). These findings support that the N-terminal LZ domain of PKGIα is required for PGKIα-mediated suppression of cardiac hypertrophy in both unstressed hearts and those exposed to pressure overload. The early mortality following TAC in the LZM mice also supports a critical role for PKGIα in attenuating pathologic cardiac remodeling, identifying PKGIα as an attractive candidate therapeutic target for prevention of cardiac hypertrophy and failure.

The nitric oxide-cGMP-dependent protein kinase pathway is a central regulator of cardiovascular physiology. Protein Kinase G I (PKGI), a principle mediator of this pathway, has been implicated as a negative regulator of cardiac hypertrophy, but the specific mechanisms involved are unknown. To test the hypothesis that PKGIα regulates cardiac hypertrophy, we characterized the cardiac phenotype of mice homozygous for a mutant form of PKGIα in which critical amino acids in the N-terminal leucine zipper (LZ) motif have been substituted to disrupt PKGIα LZ binding to specific downstream effector proteins. In the unstressed state, male PKG Iα leucine zipper mutant ( LZM) mice develop progressive LV hypertrophy compared with wild type (WT) littermates with LV mass/tibia length 12.3% greater at 30 weeks of age (p=0.05), and 27% greater at 60 weeks (p=0.001). Compared with WT littermates, the hearts of 30 week old PKGIα mutants are hypercontractile with decreased end systolic diameter (p=0.02) and increased fractional shortening on echocardiography (p=0.03). Invasive hemodynamics demonstrate that LZM mice also have increased LV systolic pressure (p=0.04), developed pressure (p=0.05), and LV dP/dt max (p=0.13). To evaluate the response to hemodynamic stress, cardiac hypertrophy was induced by transaortic constriction (TAC) in male WT and LZM mice. TAC resulted in early mortality in the LZM mice (60%) compared to the WT (19%) mice at 21 days post procedure (p=0.008), with evidence of accelerated LV hypertrophy in the mice that died early (LV mass/tibia length 9.8 mg/mm in the early LZM deaths vs 7.2 mg/mm in WT survivors, p<0.001). Additionally, the LZM early deaths had evidence of congestive heart failure with increased RV mass (RV mass/ tibia length 1.8 mg/mm in LZM early deaths vs 1.2 mg/mm in WT survivors, p<0.05), and increased lung mass (23.1 mg/mm LZM early deaths vs 12.5 mg/mm in WT survivors, p<0.005). These findings support that the N-terminal LZ domain of PKGIα is required for suppression of cardiac hypertrophy. The early mortality following TAC in the LZM mice also suggests a critical role for PKGIα in attenuating pathologic cardiac remodeling, identifying PKGIα as an attractive candidate drug target for prevention of cardiac hypertrophy and failure.