To Promote Cardiac Hypertrophy Gene A Cark The Function Of Inhibition Of The Cardiac Hypertrophy Gene Gdf15 Genetic Association Studies

CARK (Cardiac Ankyrin Repeat Kinase) is a novel gene cloned from human adult cardiovascular cDNA library. It is a highly cardiac-specific functional tyrosine kinase, which directly interacts with cardiac troponinâ… . The phylogenetic parsimony analysis indicates that CARK belongs to the closely related MAPKKKs family. Although the members of the MAPK cascade have been implicated as important regulators of cardiac hypertrophy, the effects of CARK in heart are unknown.To determine whether CARK is involved in pressure-overload-induced cardiac hypertrophy, CARK expression was examined by real-time PCR analysis in hypertrophy models in vivo and in vitro. A dramatic decrease was observed in CARK expression (0.66%) on the day 1, followed by a slowly continuously increase up to 14 days (1.62-fold) after transverse aortic constriction (TAC). The expression profile of CARK was similar in cardiomyocytes after stimulated by angiotensin-â…¡(10^-7mol/L) and phenylephrine (10^-4mol/L).To investigate the role of CARK in cardiac hypertrophy, we generated three lines of transgenic mice with cardiac-restricted overexpression of CARK, which carry 2, 8, and 44 copies of the transgene, respectively. Concentric cardiac hypertrophy was detected in all CARK transgenic mice, and the degree of hypertrophy is correlated with the number of integrated transgenic copies. In comparison with non-transgenic littermates, the ratio of heart/body weight was significantly increased of 31.3% at 3 months of age in the CARK transgenic mice with high copy number (P＜0.001). The left ventricular thickness was dramatically increased (36.3% and 47.8% increase in IVS and LVPW, respectively, P＜0.01, P＜0.01) and the left ventricular chamber dimension was significantly decreased (19.1% decrease in LVEDD, P＜0.01, and 10.6% in LVESD, P＜0.01, respectively) in high-copy-number CARK transgenic mice, as measured by M-mode echocardiography. Doppler echocardiography and closed-chest catheter revealed that the left ventricular systolic and diastolic function were significantly enhanced in high-copy-number CARK transgenic mice. The CARK transgenic mice had normal cytoarchitecture without fibrosis at 3 months of age. Moreover, the significant cardiac hypertrophy and significantly enhanced systolic function were detected in CARK transgenic mice with high copy number up to 12 months, suggesting that the cardiac hypertrophy caused by CARK over-expression did not lead to heart failure at that time, Consistent with the results in vivo, Expression of CARK in neonatal cardiomyocyte cultures by adenoviral-mediated gene transfer also induced hypertrophy in vitro. The phosphorylation of cTnl Ser23/24 and the expression of SERCa2a (sarcoplasmic reticulum Ca²⁺-ATPase) were greatly increased in the heart carrying high-copy-number CARK in the transgenic mice, suggesting CARK may be associated with the phosphorylation of sarcomere protein and activation of calcium in cardiomyocytes.In conclusion, our results indicate that CARK is involved in pressure-overload induced cardiac hypertrophy. The overexpression of CARK promotes cardiac hypertrophy in vivo and in vitro. Background—Growth-differentiation factor 15 (GDF15) is a novel antihypertrophic factor in the heart, which is induced in response to cardiac injury and play important regulatory role in the process of left ventricular hypertrophy. We hypothesized that genetic variants of GDF15 may associate with left ventricular mass and geometry in hypertension.Methods and Resuits—A Chinese community-based hypertensive population sample of 1527 individuals (506 men) aged 40 to 75 years was studied by M-mode echocardiography to assess left ventricular size and mass. The association of two tagSNP (-3148C/G and +157A/T) and one functional SNP (+2438C/G) in GDF15 gene with left ventricular remodeling were tested. Only the tagSNP -3148C/G showed a significant association with diastolic blood pressure, left ventricular hypertrophy and echocardiographic variables. Specifically, the -3148G was associated with lower level of diastolic blood pressure (CC, CG, and GG, respectively, 100.0±12.6 mmHg, 98.3±11.7 mmHg, 97.6±11.5 mmHg, P=0.015) and lower risk of left ventricular hypertrophy (OR=0.78, 95%CI 0.65-0.94, P=0.009). In multiple regression analyses, -3149G predicted statistically significant variations in left ventricular end-diastolic diameter (β=-0.10, P=0.0001), end-systolic diameter (β-0.09, P=0.0007), non-indexed mass (β=-0.11, P＜0.0001) and indexed mass (β=-0.13, P＜0.0001). These effects were independent of potentially confounding factors, including sex, age, body size, blood pressure, diabetes, anti-hypertensive treatment, cigarette and ethanol consumption. Linear regression analyses suggest a "gene dosage" effect for the -3148 G allele.Conclusions—Genetic variation within the promoter region of GDF15 gene is strongly associated with left ventricular size, mass and hypertrophy status in human essential hypertension.