Mitigation of myocardial fibrosis by molecular cardiac surgery–mediated gene overexpression

Abstract

Objective Heart failure is accompanied by upregulation of transforming growth factor beta signaling, accumulation of collagen and dysregulation of sarcoplasmic reticulum calcium ATPase cardiac isoform 2a (SERCA2a). We examined the fibrotic response in small and large myocardial infarct and the effect of overexpressing the SERCA2a gene. Methods Ischemic cardiomyopathy was induced via creation of large infarct or small infarct in 26 sheep. All animals were divided into four groups: small infarct; large infarct with heart failure; gene treated (large infarct with heart failure followed by AAV1.SERCA2a gene construct transfer by molecular cardiac surgery with recirculating delivery); and control group. Results Heart failure was significantly less pronounced in the gene treated and small infarct groups than in the large infarct group. Expression of transforming growth factor beta signaling components was significantly higher in large infarct compared to small infarct or gene treated. Further, both the angiotensin II type 1 receptor and angiotensin II were significantly elevated in small and large infarcts, while gene treatment diminished this effect. Active fibrosis with de novo collagen synthesis was evident in large infarct, while small infarct and gene treatment groups showed less fibrosis with a lower ratio of de novo to mature collagen. Conclusions The data presented supports that the progression of fibrosis is mediated through increased transforming growth factor beta and angiotensin II signaling, which is mitigated by increased SERCA2a gene expression.

Impact of oxidative posttranslational modifications of SERCA2 on heart failure exacerbation in young patients with non-ischemic cardiomyopathy: A pilot study

“…Though a causal link between OPTM of SERCA2 and myocardial fibrosis could not be drawn from the present study, these results indicate that OPTM of SERCA2 and subsequent [Ca 2+ ] c dysregulation are involved in human heart failure. This association between OPTM of SERCA2 and myocardial fibrosis is consistent with the results of a previous study showing that myocardial fibrosis was mitigated by upregulation of SERCA2 in mice [33]. Further, a recent study reported that fibroblasts exacerbate [Ca 2+ ] c dysregulation in failing myocytes by reducing SR Ca 2+ content [34].…”

Human Cardiac Gene Therapy

“…Percutaneous or surgical induction of myocardial infarction (MI) is the most widely used large animal models of acute 64–66 and chronic heart failure 53, 67–69 . However, location of coronary artery occlusion, duration of ischemia to reperfusion (ranging from <1 hr to permanent), timing of therapeutic application significantly influence disease phenotype that can result in large differences in the study outcome.…”

Introducing Genes to the Heart

“…Retrograde coronary sinus delivery of vectors during anterior coronary artery flow blockade has been shown to achieve efficient gene transduction in pigs and is being considered as a delivery method for future clinical trials 8 . Extra-corporeal recirculating devices and closed circuit retrograde infusion during bypass result in much larger viral genomes per DNA and higher transduction efficacy overall 9 . Since majority of patients who are candidates for cardiac gene therapy have impaired cardiac function, employing invasive procedures need to be cautiously considered as it directly links to safety.…”

“…Since majority of patients who are candidates for cardiac gene therapy have impaired cardiac function, employing invasive procedures need to be cautiously considered as it directly links to safety. Meanwhile, when patients need surgical procedures for coronary bypass or valve replacement surgeries, vector delivery using cardiopulmonary support device may be an effective approach 9 .…”