The investigation of an alternative inhibitor for statin resistance and intolerance

About 790,000 Americans suffer a heart attack every year, metabolic dysfunctions such as hypercholesterolemia is one of the leading cause in each case and a rising health disparity. Although different statins are available to treat hypercholesterolemia, many patients develop intolerable side effects that oblige them to abandon the treatment despite their doctors’ recommendation. The side effects are resultant of statin resistance or statin intolerance, correlated to proprotein convertase subtilisin/kexin-9 (PCSK9) gain- of-function/loss-of-function mutations. Alternative treatments to statins are the recently developed PCSK9 inhibitors. However, these biologicals are expensive, hard to qualify for, and also cause side effects due to the lack of specificity to inhibit the PCSK9 pathway involved in hypercholesterolemia development. To design more efficient and inexpensive drugs/pharmaceuticals against PCSK9, studies are needed to identify conditions and factors that may influence complex formation between PCSK9 and the low density lipoprotein (LDL) receptor, the major determinants of plasma LDL-cholesterol levels. More than 95 million Americans have hypercholesterolemia, but only 43 million are currently taking an anticholesterolemic medication. Alpha-1-antitrypsin (A1AT) is usually associated with protection against lung and hepatic disease, but recently, it was shown that low levels of A1AT cause atherosclerosis. A1AT can directly associate with LDL. Considering their contrasting role in atherosclerosis development, we should investigate whether A1AT can inhibit the function of PCSK9. Hormonal regulation of PCSK9 function has shown inhibitory actions between PCSK9 and the LDL receptor. Combining the inhibitory effect of hormones with that of A1AT would possibly result in an idealistic control of cholesterol levels which is not being fulfilled by common statin treatment at a similarly affordable rate. Based on this, we hypothesize that the levels of LDL receptor protein available to bind and remove LDL from circulation are significantly controlled by the ratio between A1AT and PCSK9 in health disparity models. The long-term objective of this research project is to characterize the molecular mechanisms involved in the A1AT -dependent regulation of PCSK9 expression and function.