Approval of Stroke and Cardiovascular Disease Control Act in Japan: Comprehensive nationwide approach for prevention, treatment, and patients' support.

The Stroke and Cardiovascular Disease Control Act was enacted in Japan in December 2018. This law has become the first ever legislative countermeasure against stroke and cardiovascular disease in Japan. The government shall make a "Basic Plan to Promote Stroke and Cardiovascular Disease Control Programs" with input from a council consisted of stakeholders. In accordance with the government plan, each prefecture shall make a prefectural plan. Both government and prefectural plans will be reviewed at least every six years. A nationwide approach is expected to contribute to reducing the burden of disease and to prolong healthy life expectancy.

Nationwide Actions Against Heart Failure Pandemic in Japan　- What Should We Do From Academia?

Heart failure pandemic is rapidly approaching in Japan, requiring nationwide actions. In particular, the Japanese Circulation Society and related societies launched the Stroke and Cardiovascular Disease Control Act, which was passed by the National Diet, as the first ever legislative policy measure against stroke and cardiovascular disease. In association with this, actions against heart failure pandemic from the scientific field are also important. Because heart failure pandemic is a critical problem not only in Japan but also in many developed countries, we believe the nationwide approach, as summarized here, will greatly contribute to the development of cardiovascular medicine, particularly the management and treatment of heart failure worldwide.

CD36 single nucleotide polymorphism is associated with variation in low-density lipoprotein-cholesterol in young Japanese men.

Macrophages uptake oxidized low-density lipoprotein (LDL) via a scavenger receptor such as CD36 from plasma, and then become foam cells. We examined the association of CD36 gene single nucleotide polymorphisms (SNPs) with certain metabolic characteristics in a young male Japanese population (n = 494). The G allele in a SNP located at +30215 on the 3'-untranslated region (UTR) was significantly correlated with the plasma LDL-cholesterol concentrations (r = 0.13, p <0.01). The difference in LDL-cholesterol concentrations was 10 mg dl(-1) between GG- and AA-genotype carriers (p <0.05). The CD36 gene SNP is a novel maker of the variation in the LDL-cholesterol levels in young Japanese men.

Serum tenascin-C might be a novel predictor of left ventricular remodeling and prognosis after acute myocardial infarction.

OBJECTIVES: We investigated clinical implications of serum tenascin-C (TN-C) levels in patients with acute myocardial infarction (AMI). BACKGROUND: Tenascin-C, an extracellular matrix glycoprotein, is not normally expressed in the adult heart, but transiently appears during pathological conditions and plays important roles in tissue remodeling. METHODS: Serum TN-C levels were measured by ELISA in 105 AMI patients at various time points, in 10 old myocardial infarction (OMI) patients, and 20 normal controls. RESULTS: The mean serum TN-C level of AMI patients on admission (63.3 +/- 30.1 ng/ml) was significantly higher than that of controls and OMI (30.9 +/- 8.8 ng/ml and 27.4 +/- 11.7 ng/ml, respectively, p < 0.01), and peaked at 5 days (83.2 +/- 43.0 ng/ml). Follow-up examination (mean: 43.9 +/- 19.6 months) revealed that 25 of 105 AMI (23.8%) patients showed left ventricular (LV) remodeling (> or =20% end-diastolic volume increase), and in 15 (14.3%), major adverse cardiac events (MACE) were detected. The peak TN-C level was significantly higher in the remodeling group than the nonremodeling group (112 +/- 37 ng/ml vs. 66 +/- 29 ng/ml; p < 0.0001). By receiver-operating characteristic (ROC) analysis, TN-C levels clearly discriminated prediction of LV remodeling and MACE compared with other variables including plasma B-type natriuretic peptide, creatine kinase-MB, and LV function. Best predictive values of TN-C for remodeling and MACE were 84.8 and 92.8 ng/ml, respectively. Cox proportional hazards model analysis showed that TN-C was an important independent predictor of MACE. CONCLUSIONS: The findings suggest that serum TN-C levels might be useful in predicting LV remodeling and prognosis after AMI.

Insulin-induced cell cycle progression is impaired in chinese hamster ovary cells overexpressing insulin receptor substrate-3.

To analyze the roles of insulin receptor substrate (IRS) proteins in insulin-stimulated cell cycle progression, we examined the functions of rat IRS-1 and IRS-3 in Chinese hamster ovary cells overexpressing the human insulin receptor. In this type of cell overexpressing IRS-1 or IRS-3, we showed that: 1) overexpression of IRS-3, but not IRS-1, suppressed the G1/S transition induced by insulin; 2) IRS-3 was more preferentially localized to the nucleus than IRS-1; 3) phosphorylation of glycogen synthase kinase 3 and MAPK/ERK was unaffected by IRS-3 overexpression, whereas that of protein kinase B was enhanced by either IRS; 4) overexpressed IRS-3 suppressed cyclin D1 expression in response to insulin; 5) among the signaling molecules regulating cyclin D1 expression, activation of the small G protein Ral was unchanged, whereas insulin-induced gene expression of c-myc, a critical component for growth control and cell cycle progression, was suppressed by overexpressed IRS-3; and 6) insulin-induced expression of p21, a cyclin-dependent kinase inhibitor, was decreased by overexpressed IRS-3. These findings imply that: 1) IRS-3 may play a unique role in mitogenesis by inhibiting insulin-stimulated cell cycle progression via a decrease in cyclin D1 and p21 expressions as well as suppression of c-myc mRNA induction in a manner independent of the activation of MAPK, protein kinase B, glycogen synthase kinase 3 and Ral; and 2) the interaction of IRS-3 with nuclear proteins may be involved in this process.

Atrial natriuretic peptide inhibits cardiomyocyte hypertrophy through mitogen-activated protein kinase phosphatase-1.

Cardiac hypertrophy is formed in response to hemodynamic overload. Although a variety of factors such as catecholamines, angiotensin II (AngII), and endothelin-1 (ET-1) have been reported to induce cardiac hypertrophy, little is known regarding the factors that inhibit the development of cardiac hypertrophy. Production of atrial natriuretic peptide (ANP) is increased in the hypertrophied heart and ANP has recently been reported to inhibit the growth of various cell types. We therefore examined whether ANP inhibits the development of cardiac hypertrophy. Pretreatment of cultured cardiomyocytes with ANP inhibited the AngII- or ET-1-induced increase in the cell size and the protein synthesis. ANP also inhibited the AngII- or ET-1-induced hypertrophic responses such as activation of mitogen-activated protein kinase (MAPK) and induction of immediate early response genes and fetal type genes. To determine how ANP inhibits cardiomyocyte hypertrophy, we examined the mechanism of ANP-induced suppression of the MAPK activation. ANP strongly induced expression of MAPK phosphatase-1 (MKP-1) and overexpression of MKP-1 inhibited AngII- or ET-1-induced hypertrophic responses. These growth-inhibitory actions of ANP were mimicked by a cyclic GMP analog 8-bromo-cyclic GMP. Taken together, ANP directly inhibits the growth factor-induced cardiomyocyte hypertrophy at least partly via induction of MKP-1. Our present study suggests that the formation of cardiac hypertrophy is regulated not only by positive but by negative factors in response to hemodynamic load.

Isolation of a chromosome 1 region affecting blood pressure and vascular disease traits in the stroke-prone rat model.

Recently, a genome-wide screen has shown a major quantitative trait locus (QTL) for a stroke-associated phenotype on rat chromosome 1 (RNO1) independent of QTL for blood pressure (BP) in the stroke-prone spontaneously hypertensive rat (SHRSP) of a Heidelberg colony. However, it remains to be elucidated whether these observations reflect the existence of different genes predisposing to each of the disorders. To address this issue, we performed comprehensive approaches in a Japanese colony, Izm, as follows. First, we undertook genome-wide searches in F1(SHRSP/IzmxWKY/Izm)xSHRSP/Izm back-cross (n=63) to pursue a causal relation between hypertension and stroke. Although the strongest linkage to BP (LOD score of 3.4) was identified on RNO1, its relevance to stroke was not supported in the F1 back-cross studied. Second, we also investigated linkage to BP in F2 progeny (n=175) involving the stroke-resistant (or normal) spontaneously hypertensive rat (SHR). In F2 studies of SHR/Izm, this locus did not appear to constitute a principal BP QTL. Third, we constructed congenic animals with detailed phenotype characterization. Transfer of a chromosomal fragment between markers Klk1 and D1Rat116 from WKY/Izm onto the SHRSP/Izm background lowered systolic BP by 20 to 80 mm Hg, prevented development of apparent stroke, and exaggerated impaired glucose tolerance. In conclusion, we have successfully isolated an RNO1 region affecting BP, stroke, and glucose tolerance in SHRSP/Izm-derived congenic rats. The size of the introgressed region is large, but our novel congenic strain should help delineate complex, genetic impairments underlying BP and associated vascular disease phenotypes.

Deficiency of protein S-mediated familial venous thrombophilia--a case report.

Deficiency of protein S causes potential problems of thrombosis. Cases of familial venous thrombosis due to deficiency of protein S were presented. First, an 85-year-old woman had pulmonary thromboembolism due to left deep femoral venous thrombosis, which might be triggered by leg fracture and the long-term treatment with a plaster cast. Next, her 29-year-old granddaughter had episodes of recurrent venous thrombosis in her legs and arms, which might be triggered by the treatment with a plaster cast and abortion. In the latter part, the aspects of risks for thromboembolism, potential problems in gestational period, and an advisability of thromboprophylaxis in patients with deficiency of protein S are described.

Cdc42 plays a critical role in assembly of sarcomere units in series of cardiac myocytes.

Cardiomyocyte hypertrophy is observed in various cardiovascular diseases and causes heart failure. We here examined the role of small GTP-binding proteins of Rho family in phenylephrine (PE)-or leukocyte inhibitory factor (LIF)-induced hypertrophic morphogenesis of cultured neonatal rat cardiomyocytes. Both LIF and PE increased cell size of cardiomyocytes. LIF induced an increase in the length/width ratio of cardiomyocytes, while PE did not change the ratio. Adenoviral gene transfer of constitutively active mutants of Cdc42 increased the length/width ratio of cardiomyocytes and dominant negative mutants of Cdc42 conversely inhibited LIF-induced cell-elongation, while mutants of RhoA and Rac1 did not affect the length/width ratio of cardiomyocytes. These results suggest that Cdc42, but not RhoA and Rac1, is involved in LIF-induced sarcomere assembly in series in cardiomyocytes.

Protection of insulin receptor substrate-3 from staurosporine-induced apoptosis.

In primary adipocytes, insulin receptor substrate (IRS)-1 and -3 are expressed in a comparable amount and play distinct roles in insulin signaling. To examine the roles of these IRS in apoptosis inhibition, we evaluated staurosporine-induced apoptosis in Chinese hamster ovary (CHO) cells overexpressing human insulin receptor and IRS-1 or IRS-3. Overexpression of both IRS protected CHO cells from staurosporine-induced apoptosis. Overexpressed IRS-3 as well as IRS-1 enhanced phosphoinositide (PI) 3-kinase activity in response to insulin and increased phosphorylation of protein kinase B (PKB) at S473 and phosphorylation of one of the members of the forkhead transcription factor FKHRL1 on T32 in both insulin-untreated and -treated states. Treatment of these cells with a PI 3-kinase inhibitor LY294002 suppressed apoptosis-inhibitory effects of IRS-1 and IRS-3 as well as the phosphorylation of PKB and FKHRL1. These results indicate that both IRS-1 and IRS-3 take part in apoptosis inhibition through the PI 3-kinase/PKB/forkhead cascade.

Resistance to neointimal hyperplasia and fatty streak formation in mice with adrenomedullin overexpression.

OBJECTIVE: Several in vitro studies have implicated that adrenomedullin (AM) plays an important role in the pathogenesis of vascular injury and fatty streak formation. To test this possibility in vivo, we evaluated 2 experimental models using transgenic mice overexpressing AM in a vessel-selective manner (AMTg mice). METHODS AND RESULTS: Placement of a periarterial cuff on femoral arteries resulted in neointimal formation at 2 to 4 weeks to a lesser extent in AMTg mice than in their wild-type littermates (at 28 days, intima/media area ratio 0.45+/-0.14 versus 1.31+/-0.41, respectively; P<0.001). This vasculoprotective effect observed in AMTg mice was inhibited by N(omega)-nitro-L-arginine methyl ester. We further examined the effect of AM on hypercholesterolemia-induced fatty streak formation by crossing AMTg mice with apolipoprotein E knockout mice (ApoEKO mice). The extent of the formation of fatty streak lesions was significantly less in ApoEKO/AMTg mice than in ApoEKO mice (percent lesion area 12.0+/-3.9% versus 15.8+/-2.8%, respectively; P<0.05). Moreover, endothelium-dependent vasodilatation as indicative of NO production was superior in AMTg/ApoEKO mice compared with ApoEKO mice. CONCLUSIONS: Taken together, our data demonstrated that AM possesses a vasculoprotective effect in vivo, which is at least partially mediated by NO.