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Inhibition of cGMP-specific phosphodiesterase 5 (PDE5) ameliorates pathological cardiac remodeling and has been gaining attention as a potential therapy for heart failure. Despite promising results in males, the efficacy of the PDE5 inhibitor sildenafil in female cardiac pathologies has not been determined and might be affected by estrogen levels, given the hormone's involvement in cGMP synthesis. Here, we determined that the heart-protective effect of sildenafil in female mice depends on the presence of estrogen via a mechanism that involves myocyte eNOS-dependent cGMP synthesis and the cGMP-dependent protein kinase Ia (PKGIα). Sildenafil treatment failed to exert antiremodeling properties in female pathological hearts from Gαq- overexpressing or pressure-overloaded mice after ovary removal; however, estrogen replacement restored the effectiveness of sildenafil in these animals. In females, sildenafil-elicited myocardial PKG activity required estrogen, which stimulated tonic cardiomyocyte cGMP synthesis via an eNOS/ soluble guanylate cyclase pathway. In contrast, eNOS activation, cGMP synthesis, and sildenafil efficacy were not estrogen dependent in male hearts. Estrogen and sildenafil had no impact on pressure-overloaded hearts from animals expressing dysfunctional PKGIα, indicating that PKGIα mediates antiremodeling effects. These results support the importance of sex differences in the use of PDE5 inhibitors for treating heart disease and the critical role of estrogen status when these agents are used in females., Introduction Heart disease is the major cause of death in women as well as in men in developed countries. However, there are sex-specific clinical characteristics, some of which may be [...]

In clinical trials, aldosterone antagonists reduce cardiovascular ischemia and mortality by unknown mechanisms. Aldosterone is a steroid hormone that signals through renal mineralocorticoid receptors (MRs) to regulate blood pressure. MRs are expressed and regulate gene transcription in human vascular cells, suggesting that aldosterone might have direct vascular effects. Using gene expression profiling, we identify the pro-proliferative VEGF family member placental growth factor (PGF) as an aldosterone-regulated vascular MR target gene in mice and humans. Aldosterone-activated vascular MR stimulated Pgf gene transcription and increased PGF protein expression and secretion in the mouse vasculature. In mouse vessels with endothelial damage and human vessels from patients with atherosclerosis, aldosterone enhanced expression of PGF and its receptor, FMS-like tyrosine kinase 1 (Flt1). In atherosclerotic human vessels, MR antagonists inhibited PGF expression. In vivo, aldosterone infusion augmented vascular remodeling in mouse carotids following wire injury, an effect that was lost in [Pgf.sup.-/-] mice. In summary, we have identified PGF as what we believe to be a novel downstream target of vascular MR that mediates aldosterone augmentation of vascular injury. These findings suggest a non-renal mechanism for the vascular protective effects of aldosterone antagonists in humans and support targeting the vascular aldosterone/MR/PGF/Flt1 pathway as a therapeutic strategy for ischemic cardiovascular disease., Introduction In heart failure trails, in addition to reducing cardiovascular mortality, aldosterone antagonists have also been unexpectedly shown to significantly reduce atherosclerotic clinical events by mechanisms that remain unclear (1), [...]

The heart initially compensates for hypertension-mediated pressure overload by enhancing its contractile force and developing hypertrophy without dilation. [G.sub.q] protein--coupled receptor pathways become activated and can depress function, leading to cardiac failure. Initial adaptation mechanisms to reduce cardiac damage during such stimulation remain largely unknown. Here we have shown that this initial adaptation requires regulator of G protein signaling 2 (RGS2). Mice lacking RGS2 had a normal basal cardiac phenotype, yet responded rapidly to pressure overload, with increased myocardial [G.sub.q] signaling, marked cardiac hypertrophy and failure, and early mortality. Swimming exercise, which is not accompanied by [G.sub.q] activation, induced a normal cardiac response, while Rgs2 deletion in [G.sub.[alpha]q]-overexpressing hearts exacerbated hypertrophy and dilation. In vascular smooth muscle, RGS2 is activated by cGMP-dependent protein kinase (PKG), suppressing [G.sub.q]-stimulated vascular contraction. In normal mice, but not Rgs2-/- mice, PKG activation by the chronic inhibition of cGMP-selective phosphodiesterase 5 (PDE5) suppressed maladaptive cardiac hypertrophy, inhibiting [G.sub.q]-coupled stimuli. Importantly, PKG was similarly activated by PDE5 inhibition in myocardium from both genotypes, but PKG plasma membrane translocation was more transient in Rgs2-/- myocytes than in controls and was unaffected by PDE5 inhibition. Thus, RGS2 is required for early myocardial compensation to pressure overload and mediates the initial antihypertrophic and cardioprotective effects of PDE5 inhibitors., Introduction The adult heart responds to sustained pressure overload by developing ventricular hypertrophy. The signaling events mediating this process are substantially driven by activation of GPCRs, which in turn stimulate [...]

Left ventricular (LV) remodeling after myocardial infarction (MI) results from hypertrophy of myocytes and activation of fibroblasts induced, in part, by ligand stimulation of the ANG II type 1 receptor (A[T.sub.1]R). The purpose of the present study was to explore the specific role for activation of the A[T.sub.1a]R subtype in post-MI remodeling and whether gender differences exist in the patterns of remodeling in wild-type and A[T.sub.1a]R knockout (KO) mice. A[T.sub.1a]R-KO mice and wild-type littermates underwent coronary ligation to induce MI or sham procedures; echocardiography and hemodynamic evaluation were performed 6 wk later, and LV tissue was harvested for infarct size determination, morphometric measurements, and gene expression analysis. Survival and infarct size were similar among all male and female wild-type and A[T.sub.1a]R-KO mice. Hemodynamic indexes were also similar except for lower systolic blood pressure in the A[T.sub.1a]R-KO mice compared with wild-type mice. Male and female wild-type and male A[T.sub.1a]R-KO mice developed similar increases in LV chamber size, LV mass corrected for body weight (LV/BW), and myocyte cross-sectional area (CSA). However, female A[T.sub.1a]R-KO mice demonstrated no increase in LV/BW and myocyte CSA post-MI compared with shams. Both male and female wild-type mice demonstrated higher atrial natriuretic peptide (ANP) levels after MI, with female wild types being significantly greater than males. However, male and female A[T.sub.1a]R-KO mice developed no increase in ANP gene expression with MI despite an increase in LV mass and myocyte size in males. These data support that gender-specific patterns of LV and myocyte hypertrophy exist after MI in mice with a disrupted A[T.sub.1a]R gene, and suggest that myocyte hypertrophy post-MI in females relies, in part, on activation of the A[T.sub.1a]R. Further work is necessary to explore the potential mechanisms underlying these gender-based differences. angiotensin II receptors; ventricular remodeling; myocyte; hypertrophy

Cardiovascular diseases (CVDs), the major cause of morbidity and mortality for both men and women, occur uncommonly in premenopausal women, but their incidence rises sharply after the menopausal transition. Cardiovascular gender differences are apparent long before CVDs appear in men and women, and improved understanding of the biology underlying these differences has the potential to advance the diagnosis and treatment of CVDs in both sexes. This review considers gender differences in the molecular and cellular physiology of the heart and blood vessels in health and disease, highlighting understudied areas that can help resolve the current controversy regarding hormone replacement therapy and improve cardiovascular health in women., Sex Steroid Hormones, Receptors, and Gender Differences Women develop heart disease later in life than men. This difference has been attributed to the loss of female sex steroid hormones at [...]

Steroid hormone receptors (SHRs) are ligand-activated transcription factors that regulate gene expression. SHRs also mediate rapid, nongenomic cellular activation by steroids. In vascular endothelial cells, the SHR for estrogen, estrogen receptor (ER) [alpha], is targeted by unknown mechanisms to a functional signaling module in membrane caveolae that enables estrogen to rapidly activate the mitogen-activated protein kinase and phosphatidylinositol 3-Akt kinase pathways, and endothelial NO synthase (eNOS). Here we identify the 110-kDa caveolin-binding protein striatin as the molecular anchor that localizes ER[alpha] to the membrane and organizes the ER[alpha]-eNOS membrane signaling complex. Striatin directly binds to amino acids 183-253 of ER[alpha], targets ER[alpha] to the cell membrane, and serves as a scaffold for the formation of an ER[alpha]-G[alpha]i complex. Disruption of complex formation between ER[alpha] and striatin blocks estrogen-induced rapid activation mitogen-activated protein kinase, Akt kinase, and eNOS, but has no effect on ER-dependent regulation of an estrogen response element-driven reporter plasmid. These findings identify striatin as a molecular scaffold required for rapid, nongenomic estrogen-mediated activation of downstream signaling pathways. Furthermore, by demonstrating independent regulation of nongenomic vs. genomic ER-dependent signaling, these findings provide conceptual support for the potential development of 'pathway-specific' selective ER modulators.

Nitric oxide (NO) inhibits vascular contraction by activating cGMP-dependent protein kinase I-[alpha] (PKGI-[alpha]), which causes dephosphorylation of myosin light chain (MLC) and vascular smooth muscle relaxation. Here we show that PKGI-[alpha] attenuates signaling by the thrombin receptor protease-activated receptor-1 (PAR-1) through direct activation of regulator of G-protein signaling-2 (RGS-2). NO donors and cGMP cause cGMP-mediated inhibition of PAR-1 and membrane localization of RGS-2. PKGI-[alpha] binds directly to and phosphorylates RGS-2, which significantly increases GTPase activity of G[sub.q], terminating PAR-1 signaling. Disruption of the RGS-2-PKGI-[alpha] interaction reverses inhibition of PAR-1 signaling by nitrovasodilators and cGMP. Rgs2[sup.-/-] mice develop marked hypertension, and their blood vessels show enhanced contraction and decreased cGMP-mediated relaxation. Thus, PKGI-[alpha] binds to, phosphorylates and activates RGS-2, attenuating receptor-mediated vascular contraction. Our study shows that RGS-2 is required for normal vascular function and blood pressure and is a new drug development target for hypertension., Author(s): Mary Tang [1]; Guang Wang [1]; Ping Lu [1, 4]; Richard H Karas [1]; Mark Aronovitz [1]; Scott P Heximer [2]; Kevin M Kaltenbronn [2]; Kendall J Blumer [2]; [...]

A mutation in the gene for the estrogen receptor may increase a person's risk of developing heart disease, according to a study of 1,739 men and women. A total of 352 of the men and women had a particular mutation in the estrogen receptor alpha gene and they were twice as likely as the others to develop atherosclerosis. They were three times more likely to have a heart attack as those who did not have the mutation.

Blood vessels express estrogen receptors, but their role in cardiovascular physiology is not well understood. We show that vascular smooth muscle cells and blood vessels from estrogen receptor β (ER β)-deficient mice exhibit multiple functional abnormalities. In wild-type mouse blood vessels, estrogen attenuates vasoconstriction by an ER β-mediated increase in inducible nitric oxide synthase expression, in contrast, estrogen augments vasoconstriction in blood vessels from ER Β-deficient mice. Vascular smooth muscle cells isolated from ER β-deficient mice show multiple abnormalities of ion channel function. Furthermore, ER β-deficient mice develop sustained systolic and diastolic hypertension as they age. These data support an essential role for ER β in the regulation of vascular function and blood pressure., Steroid hormones regulate a wide range of cellular events by activating a receptor family of transcription factors (1). Estrogens influence gene expression, growth, and cellular differentiation in target tissues by [...]

Atherosclerosis is the primary cause of cardiovascular disease, and the risk for atherosclerosis is inversely proportional to circulating levels of high-density lipoprotein (HDL) cholesterol. However, the mechanisms by which HDL is atheroprotective are complex and not well understood. Here we show that HDL stimulates endothelial nitric oxide synthase (eNOS) in cultured endothelial cells. In contrast, eNOS is not activated by purified forms of the major HDL apolipoproteins ApoA-I and ApoA-II or by low-density lipoprotein. Heterologous expression experiments in Chinese hamster ovary cells reveal that scavenger receptor-BI (SR-BI) mediates the effects of HDL on the enzyme. HDL activation of eNOS is demonstrable in isolated endothelial-cell caveolae where SR-BI and eNOS are colocalized, and the response in isolated plasma membranes is blocked by antibodies to ApoA-I and SR-BI, but not by antibody to ApoA-II. HDL also enhances endothelium- and nitric-oxide-dependent relaxation in aortae from wild-type mice, but not in aortae from homozygous null SR-BI knockout mice. Thus, HDL activates eNOS via SR-BI through a process that requires ApoA-I binding. The resulting increase in nitric-oxide production might be critical to the atheroprotective properties of HDL and ApoA-I., Author(s): Ivan S. Yuhanna [1]; Yan Zhu [4]; Blair E. Cox [1]; Lisa D. Hahner [1]; Sherri Osborne-Lawrence [1]; Ping Lu [4]; Yves L. Marcel [5]; Richard G.W. Anderson [3]; [...]

Ovine fetal pulmonary artery endothelial cells were permanently transfected with the E6 and E7 open reading frames of human papillomavirus type 16 in an effort to establish an immortalized cell line. This is because investigation of fetal pulmonary endothelial cell gene expression and function has been limited by the requirement for primary cells. The results showed that immortalized pulmonary artery endothelial cells will provide an excellent model for further studies of endothelial nitric oxide synthase gene expression and function in fetal pulmonary endothelium.

Estrogen appears to have a direct influence on blood vessels. Estrogen was believed to protect women from heart disease by lowering blood levels of fats that cause atherosclerosis. However, research shows that the hormone also relaxes blood vessels, causing them to expand. Estrogen may not exert this effect directly but via other proteins and chemicals that are produced when estrogen binds to its receptor. One such chemical is nitric oxide, which also relaxes blood vessels. Estrogen also affects proteins involved in blood clotting and the breakdown of blood clots.

Phosphodiesterase 5 inhibition (PDE5i) activates cGMP‐dependent protein kinase (PKG) and ameliorates heart failure; however, its impact on cardiac mitochondrial regulation has not been fully determined. Here, we investigated the role of the mitochondrial regulator peroxisome proliferator‐activated receptor γ co‐activator‐1α (PGC1α) in the PDE5i‐conferred cardioprotection, utilizing PGC1α null mice. In PGC1α+/+ hearts exposed to 7 weeks of pressure overload by transverse aortic constriction, chronic treatment with the PDE5 inhibitor sildenafil improved cardiac function and remodeling, with improved mitochondrial respiration and upregulation of PGC1α mRNA in the myocardium. By contrast, PDE5i‐elicited benefits were abrogated in PGC1α−/− hearts. In cultured cardiomyocytes, PKG overexpression induced PGC1α, while inhibition of the transcription factor CREB abrogated the PGC1α induction. Together, these results suggest that the PKG–PGC1α axis plays a pivotal role in the therapeutic efficacy of PDE5i in heart failure. [ABSTRACT FROM AUTHOR]

Left coronary ligation or a sham procedure were conducted on normal C57BL/6J mice. After six weeks, the mice underwent echocardiography and hemodynamic evaluation. Findings illustrated the applicability of ventricular remodeling in a mouse model of myocardial infarction and confirmed the possibility of quantifying indexes of modeling in vivo and postmortem. This model will be very useful for transgenic strains.