angiotensinogen and Dyslipidemias

Sudden cardiac death (SCD) is the leading global cause of mortality, exhibiting increased incidence in patients with diabetes mellitus. Ion channel gene perturbations provide a well-established ventricular arrhythmogenic substrate for SCD. However, most arrhythmia-susceptibility genes, including the KCNE2 K(+) channel β subunit, are expressed in multiple tissues, suggesting potential multiplex SCD substrates.. Using whole-transcript transcriptomics, we uncovered cardiac angiotensinogen upregulation and remodeling of cardiac angiotensinogen interaction networks in P21 Kcne2(-/-) mouse pups and adrenal remodeling consistent with metabolic syndrome in adult Kcne2(-/-) mice. This led to the discovery that Kcne2 disruption causes multiple acknowledged SCD substrates of extracardiac origin: diabetes mellitus, hypercholesterolemia, hyperkalemia, anemia, and elevated angiotensin II. Kcne2 deletion was also a prerequisite for aging-dependent QT prolongation, ventricular fibrillation and SCD immediately after transient ischemia, and fasting-dependent hypoglycemia, myocardial ischemia, and AV block.. Disruption of a single, widely expressed arrhythmia-susceptibility gene can generate a multisystem syndrome comprising manifold electric and systemic substrates and triggers of SCD. This paradigm is expected to apply to other arrhythmia-susceptibility genes, the majority of which encode ubiquitously expressed ion channel subunits or regulatory proteins.

Topics: Anemia; Angiotensin II; Angiotensinogen; Animals; Arrhythmias, Cardiac; Death, Sudden, Cardiac; Diabetes Mellitus; Dyslipidemias; Gene Regulatory Networks; Genotype; Heterozygote; Hyperkalemia; Ischemia; Long QT Syndrome; Mice; Mice, Knockout; Potassium Channels, Voltage-Gated

The genes associated with hypertension could be genetic risk factors for metabolic syndrome (MetS).. To determine the frequency of M235T and T174M-AGT, I/D-ACE and A1166C-AGTR1 in hypertensive patients with MetS and to evaluate the relationship between these polymorphisms and central obesity and dyslipidemia, respectively.. We performed AGT, AGTR1 and ACE genotyping in 56 hypertensive women (24 with MetS) and 71 normotensive women using PCR-RFLP methods and PCR, respectively.. Hypertensive patients carrying the mutated TT235, MM174 and DD genotypes had an 1.53 (p=0.56), 1.78 (p=0.52) and 1.28 (p=0.78)-fold increased risk to develop MetS. Hypertensive carriers of both mutated TT235 and MM174 or TT235 and D/D or TT235 and CC+AC genotypes had an 8.15 (p=0.04), 4.83 (p=0.04) and 10.53 (p=0.05)-fold increased risk to develop MetS. Hypertensive patients with MetS and TT, D/D or CC genotypes had higher body mass index compared to hypertensive patients without MetS (p

Topics: Adult; Angiotensinogen; Dyslipidemias; Female; Genetic Predisposition to Disease; Genotype; Humans; Hypertension, Renal; Metabolic Syndrome; Middle Aged; Obesity; Peptidyl-Dipeptidase A; Polymerase Chain Reaction; Polymorphism, Restriction Fragment Length; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Risk Factors