natriuretic-peptide--c-type and Hypertrophy--Left-Ventricular

Most cardiovascular traits of interest can be defined as "complex traits," with the first step in the identification of genetic factors affecting such traits being the detection of quantitative trait loci (QTLs). Animal models have proven particularly useful in this regard. However, only very few of the QTLs identified to date have led to the identification of candidate genes. We describe an example of our own work where the combination of anatomical and a biochemical intermediate phenotypes have led to the identification of the natriuretic peptide precursor A (Nppa) gene as a candidate gene for left ventricular hypertrophy (LVH). Combined with the power of comparative genetics, these strategies will continue to improve the chances of finding candidate genes for cardiovascular traits such as susceptibility to heart diseases, hypertension, and hypertension-induced end-organ damage.

Topics: Animals; Atrial Natriuretic Factor; Genetic Predisposition to Disease; Genotype; Humans; Hypertension; Hypertrophy, Left Ventricular; Models, Animal; Natriuretic Peptide, C-Type; Phenotype; Protein Precursors; Quantitative Trait, Heritable

Elevated levels of ambient co-pollutants are associated with adverse cardiovascular outcomes shown by epidemiology studies. The role of particulate matter (PM) and ozone (O3) as co-pollutants in this association is unclear. We hypothesize that cardiac function following PM and O3 exposure is variably affected by genetic determinants (Nppa and Npr1 genes) and age. Heart function was measured before and after 2 days each of the following exposure sequence; (1) 2-h filtered air (FA) and 3-h carbon black (CB; 0.5 microg/m(3)); (2) 2-h O3 (0.6 ppm) and 3-h FA; (3) 5-h FA; and, (4) 2-h O3 and 3-h CB. Two age groups (5 and 18 months old (mo)) were tested in C57Bl/6J (B6) and 129S1/SvImJ (129) mice using echocardiographic (echo) and in vivo hemodynamic (IVH) measurements. With echo, posterior wall thickness was significantly (P < 0.01) greater in 129 relative to B6 mice at baseline. With CB exposure, young B6 and older 129 mice show significant (P < 0.01) reductions in fractional shortening (FS) compared to FA. With O3 exposure, FS was significantly (P < 0.01) diminished in young 129, which was attributable to significant increases in end-systolic left ventricular diameter. With O3 and CB combined, notable (P < 0.01) declines in heart rate and end-systolic posterior wall thickness occurred in young 129 mice. The IVH measurements showed striking (P < 0.05) compromises in cardiac function after CB and O3 exposure; however, strain differences were undetectable. These results suggest that PM and O3 exposures, alone and combined, lead to different cardiac functional changes, and these unique changes are age-specific and dependent on Nppa and Npr1 genes.

Topics: Aging; Air Pollutants; Animals; Atmosphere Exposure Chambers; Atrial Natriuretic Factor; Cardiovascular System; Echocardiography; Female; Heart; Hemodynamics; Hypertrophy, Left Ventricular; Inhalation Exposure; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Natriuretic Peptide, C-Type; Ozone; Particulate Matter; Protein Precursors; Receptors, Atrial Natriuretic Factor; Soot; Species Specificity; Ventricular Remodeling

Mutations in a sarcomeric protein can cause hypertrophic cardiomyopathy (HCM) or dilated cardiomyopathy (DCM), the opposite ends of a spectrum of phenotypic responses of the heart to mutations. We posit the contracting phenotypes could result from differential effects of the mutant proteins on interactions among the sarcomeric proteins. To test the hypothesis, we generated transgenic mice expressing either cardiac troponin T (cTnT)-Q92 or cTnT-W141, known to cause HCM and DCM, respectively, in the heart.. We phenotyped the mice by echocardiography, histology and immunoblotting, and real-time polymerase chain reaction. We detected interactions between the sarcomeric proteins by co-immunoprecipitation and determined Ca2+ sensitivity of myofibrillar protein ATPase activity by Carter assay. The cTnT-W141 mice exhibited dilated hearts and decreased systolic function. In contrast, the cTnT-Q92 mice showed smaller ventricles and enhanced systolic function. Levels of cardiac troponin I, cardiac alpha-actin, alpha-tropomyosin, and cardiac troponin C co-immunoprecipitated with anti-cTnT antibodies were higher in the cTnT-W141 than in the cTnT-Q92 mice, as were levels of alpha-tropomyosin co-immunoprecipitated with an anti-cardiac alpha-actin antibody. In contrast, levels of cardiac troponin I co-immunoprecipitated with an anti-cardiac alpha-actin antibody were higher in the cTnT-Q92 mice. Ca2+ sensitivity of myofibrillar ATPase activity was increased in HCM but decreased in DCM mice compared with non-transgenic mice.. Differential interactions among the sarcomeric proteins containing cTnT-Q92 or cTnT-W141 are responsible for the contrasting phenotypes of HCM or DCM, respectively.

Topics: Adenosine Triphosphatases; Animals; Atrial Natriuretic Factor; Calcium; Cardiomyopathy, Dilated; Disease Models, Animal; Heart Ventricles; Hypertrophy, Left Ventricular; Mice; Mice, Transgenic; Mutation; Natriuretic Peptide, C-Type; Phenotype; Protein Precursors; Sarcomeres; Troponin T; Ultrasonography

Natriuretic peptides (NP) mediate their effects by activating membrane-bound guanylyl cyclase-coupled receptors A (NPR-A) or B (NPR-B). Whereas the pathophysiological role of NPR-A has been widely studied, only limited knowledge on the cardiovascular function of NPR-B is available. In vitro studies suggest antiproliferative and antihypertrophic actions of the NPR-B ligand C-type NP (CNP). Because of the lack of a specific pharmacological inhibitor, these effects could not clearly be attributed to impaired NPR-B signaling. Recently, gene deletion revealed a predominant role of NPR-B in endochondral ossification and development of female reproductive organs. However, morphological abnormalities and premature death of NPR-B-deficient mice preclude detailed cardiovascular phenotyping. In the present study, a dominant-negative mutant (NPR-BDeltaKC) was used to characterize CNP-dependent NPR-B signaling in vitro and in transgenic rats. Here we demonstrate that reduced CNP- but not atrial NP-dependent cGMP response attenuates antihypertrophic potency of CNP in vitro. In transgenic rats, NPR-BDeltaKC expression selectively reduced NPR-B but not NPR-A signaling. NPR-BDeltaKC transgenic rats display progressive, blood pressure-independent cardiac hypertrophy and elevated heart rate. The hypertrophic phenotype is further enhanced in chronic volume overload-induced congestive heart failure. Thus, this study provides evidence linking NPR-B signaling to the control of cardiac growth.

Topics: Animals; Animals, Genetically Modified; Blood Pressure; Bone Development; Cyclic GMP; Genes, Dominant; Guanylate Cyclase; Heart Rate; Heart Ventricles; Hypertrophy, Left Ventricular; Kidney; Mutation; Natriuretic Peptide, C-Type; Rats; Receptors, Atrial Natriuretic Factor; Sequence Deletion

Wistar-Kyoto (WKY) and WKY-derived hyperactive (WKHA) rats are two genetically-related inbred strains of rats that are both normotensive yet exhibit differences in left ventricular mass (LVM). We had shown previously that cardiomyocytes from male WKHA are wider than that of male WKY, and that there was genetic linkage between LVM and a locus on chromosome 5 (RNO5) in the male progeny of a F2 WKHA/WKY cross. We show here that cardiomyocyte width is linked to the same RNO5 locus in male reciprocal congenic rats derived from WKHA and WKY. Contrary to males, we found no genetic linkage between LVM and the RNO5 locus in female rats. However, ventricular hypertrophy in females might be of a different nature, because cardiomyocytes from female WKHA were shorter than their WKY counterparts (with no difference in width). The RNO5 locus contains that of the natriuretic peptide precursor A (Nppa) gene. In male congenic rats, changes in cardiomyocyte width always correlated with reciprocal changes in the LV concentration of atrial natriuretic factor (ANF, i.e., the peptide product of Nppa). Taken together with other functional data, the small size of the RNO5 locus (approximately 63 cR) increased the likelihood that both cardiomyocyte width and LV ANF concentration could be linked to only one gene (possibly Nppa) in male rats. Moreover, our results support the notion that genes and sex interact to regulate cardiomyocyte width and length independently from one another.

Topics: Animals; Animals, Congenic; Atrial Natriuretic Factor; Chromosome Mapping; Female; Genetic Linkage; Heart Ventricles; Hypertrophy, Left Ventricular; Male; Natriuretic Peptide, C-Type; Protein Precursors; Quantitative Trait Loci; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Reproducibility of Results; Sex Factors; Species Specificity