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Novel approaches to study myocardial hypertrophy towards development of anti‐hypertensive drugs: Expression of myosin light chain genes during cardiac hypertrophy
Author(s) -
Kumar C. Chandra
Publication year - 1989
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/ddr.430180403
Subject(s) - muscle hypertrophy , medicine , gene expression , endocrinology , biology , myosin light chain kinase , myosin , messenger rna , adrenergic , stimulation , diastole , gene , receptor , microbiology and biotechnology , blood pressure , genetics
Myocardial hypertrophy as an adaptive response to various physiological and pathological conditions is characterized by major alterations in the cellular restructuring of the heart as well as by many biochemical and genetic alterations. Hence, the development of hypertrophy provides a unique opportunity to study the various mechanisms underlying the functions of the normal and diseased heart, as well as to understand the molecular mechanisms that operate to regulate cardiac specific gene expression. Both the spontaneously hypertensive rat strain (SHR) and the myocardial cell culture system developed by Paul Simpson have been used as model systems to study cardiac specific gene expression. We have isolated and characterized in detail the rat ventricular specific myosin light chain (MLC)‐1 and MLC‐2 cDNA clones. Using a sensitives S1 nuclease analysis we have shown that while no MLC‐1 mRNA of the ventricular type is detectable in the normal and SHR atrial muscle, there is a selective increase in ventricular MLC‐2 mRNa in both 6 week old (prehypertensive stage) and 18 week old (hypertensive) SHR heart atria. The myocardial cell culture system has been used to examine the effects of α‐adrenergic stimulation on the accumulation of contractile units and the expression of MLC‐2 gene. Stimulation of α‐adrenergic receptors with norepinephrine results in an increase in cellular MLC‐2 protein content as well as an increase in steady‐state level of MLC‐2 mRNA. This increase in MLC‐2 mRNA is mediated in part by an increase in transcription of the MLC‐2 gene. In order to characterize the regulatory elements of the MLC‐2 gene, we have characterized in detail the genomic clone corresponding to rat cardiac MLC‐2 cDNA. The results show a complete conservation of exon and intron organizations between cardiac and skeletal MLC‐2 genes. There is also a strong conservation of DNA sequence elements upstream to the transcription initiation site between rat cardiac and chicken cardiac MLC‐2 genes. Analysis of the cis ‐ and trans ‐acting factors that regulate MLC‐2 gene expression during cardiac hypertrophy should prove very useful in understanding the molecular mechanisms involved in hypertropic response.