Functional Genomics of Cardioprotection by Ischemic Conditioning and the Influence of Comorbid Conditions: Implications in Target Identification

Abstract

Ischemic heart disease including myocardial infarction develops on the basis of several risk-factors and comorbidities such as obesity, diabetes, hypertension, and hypercholesterolemia. Ischemic heart disease is the leading cause of mortality worldwide, therefore, identification of novel drug targets for cardioprotection is of great importance. Ischemic preconditioning, postconditioning, and remote conditioning trigger endogenous cardioprotective mechanisms that render the heart more resistant to lethal ischemic-reperfusion injury. However, major cardiovascular co-morbidities such as hyperlipidemia, diabetes, and their co-medications interfere with these cardioprotective mechanisms thereby limiting the efficacy of cardioprotective ischemic conditioning maneuvers. Ischemia reperfusion injury and cardioprotection by conditioning have been shown to affect global myocardial gene expression profile at the transcript level. Further understanding and the comprehensive analysis of the cardioprotective gene expression fingerprint in normal, protected, and in comorbid conditions may lead to identification of novel molecular targets for cardioprotection.

Practical guidelines for rigor and reproducibility in preclinical and clinical studies on cardioprotection

“…Currently, transcriptomics seems to be useful for unbiased mechanistic studies at the transcript level, including coding or non-coding RNAs, since current technologies allow full and accurate assessment of all transcripts in biological samples [333, 337, 432, 433]. Transcriptomics can be performed by different techniques [337].…”

Epigenomic and transcriptomic approaches in the post-genomic era: path to novel targets for diagnosis and therapy of the ischaemic heart? Position Paper of the European Society of Cardiology Working Group on Cellular Biology of the Heart

“…Likewise, cardiac regeneration has the therapeutic potential to prevent the development of post-ischaemic heart failure 5 . The lack of successful translation of promising therapeutic strategies to the clinical arena includes several factors such as the use of hypothesis-driven, biased target discovery 6 , 7 and neglecting the interfering effects of common cardiovascular risk factors and their routine medications with cardioprotective pathways 4 , 8 . Therefore, for successful development of cardioprotective therapies for acute myocardial ischaemia/reperfusion injury and ischaemic heart failure, new ways to discover valid targets must be used.…”

“…Since the completion of the Human Genome Project (HGP) 9 a tremendous effort has been undertaken through Genetics, Genomics, and Functional Genomics studies to determine how this information might be linked to a healthy or unhealthy cardiac phenotype, particularly in myocardial ischaemia/reperfusion and the failing ischaemic heart 6 . Despite great expectations, so far the clinical translation of basic discoveries in the areas of genetics has produced disappointing results (previously addressed by a Scientific Statement from the American Heart Association, 10 and not discussed here).…”

Cardioprotection by gene therapy

“…Mimicking ischemic cardiac conditioning through prophylactic transfection of cardioprotective genes into the myocardium would represent a therapeutic tool to protect the heart throughout an ischemia/reperfusion episode. A thorough knowledge of the genes and signaling pathways associated with IRI and ischemic conditioning are a prerequisite for the development of cardioprotective gene therapy [1]. (See Fig.…”