Effects of genetic transfection on calcium cycling pathways mediated by double-stranded adeno-associated virus in postinfarction remodeling – DocWire…

OBJECTIVE:

Restoring calcium sensor protein (S100A1) activity in failing heartsposes a promising therapeutic strategy. We hypothesize that cardiac overexpression of the S100A1 gene mediated by a double-stranded adeno-associated virus (scAAV) results in better functional and molecular improvements compared with the single-stranded virus (ssAAV).

Heart failure was induced by coronary artery ligation. Then, intramyocardial injections of saline, AAV9 empty capsid, scAAV9.S100A1, and ssAAV9.S100A1 were performed. Ten weeks postinfarction, all rats received cardiac evaluation; serum and tissue were collected for genetic analysis, cytokine profiling, and assessments of mitochondrial function and structure.

Overexpression of AAV9.S100A1 improved systolic and diastolic function. Compared with control, ejection fraction was greater in treated groups (54.8% vs 32.3%, P<.05). Similarly, end-diastolic volume index was significantly less in the treated group than in control (1.14 vs 1.59mL/cm2), whereas fractional shortening was greater in treated groups than control (26% vs 38%, P<.05). Interestingly, cardiac mechanics were significantly better when treated with double-stranded virus compared with single-stranded. Quantitative polymerase chain reaction demonstrated robust transfection of myocardium with the S100A1 gene, with more infection in the self-complimentary group compared with the single-stranded group (5.680.44 vs 4.090.25 log10genome copies per 100ng of DNA; P<.0001). Concentrations of the inflammatory cytokines were elevated in the ssAAV9/S100A1 group compared with the scAAV9/S100A1. Assessment of mitochondrial respiration and morphology demonstrated that injection of self-complementary vector saved both mitochondrial structure and function.

Gene therapy of S100A1 can prevent pathologic postmyocardialinfarctionremodeling and decrease inflammatory response in ischemic heart failure.

Robert Dillard is a writer for DocWire News with experience in public relations and writing in the health care space.

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Effects of genetic transfection on calcium cycling pathways mediated by double-stranded adeno-associated virus in postinfarction remodeling - DocWire...