HJ. iNOS in cardiac myocytes plays a critical role in death in a murine model of hypertrophy induced by calcineurin. Am J Physiol Heart Circ Physiol 295: H1122-H1131, 2008. First published July 11, 2008 doi:10.1152/ajpheart.00386.2008.-Transgenic overexpression of calcineurin (CN/Tg) in mouse cardiac myocytes results in hypertrophy followed by dilation, dysfunction, and sudden death. Nitric oxide (NO) produced via inducible NO synthase (iNOS) has been implicated in cardiac injury. Since calcineurin regulates iNOS expression, and since phenotypes of mice overexpressing iNOS are similar to CN/Tg, we hypothesized that iNOS is pathogenically involved in cardiac phenotypes of CN/Tg mice. CN/Tg mice had increased serum and cardiac iNOS levels. When CN/Tg-iNOS Ϫ/Ϫ and CN/Tg mice were compared, some phenotypes were similar: extent of hypertrophy and fibrosis. However, CN/Tg-iNOS Ϫ/Ϫ mice had improved systolic performance (P Ͻ 0.001) and less heart block (P Ͻ 0.0001); larger sodium current density and lower serum TNF-␣ levels (P Ͻ 0.03); and less apoptosis (P Ͻ 0.01) resulting in improved survival (P Ͻ 0.0003). To define tissue origins of iNOS production, chimeric lines were generated. Bone marrow (BM) from wild-type or iNOS Ϫ/Ϫ mice was transplanted into CN/Tg mice. iNOS deficiency restricted to BMderived cells was not protective. Calcineurin activates the local production of NO by iNOS in cardiac myocytes, which significantly contributes to sudden death, heart block, left ventricular dilation, and impaired systolic performance in this murine model of cardiac hypertrophy induced by the overexpression of calcineurin. heart block; sodium current; sudden death; inducible nitric oxide synthase; transgenic overexpression of calcineurin TRANSGENIC OVEREXPRESSION of constitutively active calcineurin (CN/Tg) in cardiac myocytes results in profound concentric hypertrophy followed by ventricular dilatation, interstitial fibrosis, heart failure, and eventually sudden cardiac death (13,26,32,33,40). The sudden deaths relate to ion channelopathies, which are downstream consequences of abnormalities of calcium homeostasis (17) and an inflammatory process (6, 10, 27, 36).Previous studies indicate that inducible nitric oxide (NO) synthase (iNOS) is a downstream target of calcineurin (12,19,36,44,45). The regulation of the iNOS gene promoter by calcineurin has been reported (36). LPS-induced iNOS expression in the heart was abrogated by the pharmacological inhibition of calcineurin (36). Similarly, LPS induced the expression of iNOS in wild-type (WT) hearts but not in the calcineurin A␤ knockout hearts (36). Reciprocally, the overexpression of constitutively active calcineurin in isolated cardiomyocytes caused the dephosphorylation and nuclear accumulation of the transcription factor family originally defined as nuclear factor of activated T-cells (NFAT)c1 and induced strong iNOS expression (36). In addition, chromatin immunoprecipitation confirmed the calcineurin-dependent binding of NFATc1 to the iNOS promoter (36). These data are co...

In this study, we introduce the concept of differentiated quality inputs with knowledge-driven specifications for research and development (R&D) under an open economy to the endogenous growth model of knowledge spillover. Using matching industry enterprise and customs data from 2001 to 2007, which is representative of micro data at the Chinese industry level, we theoretically analyze the influence of the quality and variety of imported products on Chinese enterprises’ innovation and economic growth. We find that, first, the improvement of the quality and variety of new imported products can promote enterprise innovation. Second, new imported intermediate inputs and capital goods, new imported high-technology products, and products imported from Organization for Economic Co-operation and Development (OECD) countries have stronger promoting effects on enterprise innovation. We conclude that imported products stimulate the growth of the economy through two channels: expanding the variety and increasing the quality of inputs. To verify the stability of our model, we conducted robustness tests by defining new imported products based on a base year, measuring enterprise innovation by the number of patent applications, and measuring the quality of new imported products in a new way.