PRORENIN is a completely inactive form of renin that circulates in human plasma in concentrations close to 10 times that of active renin. A similar inactive form of renin appears to be secreted from the kidney, but an extrarenal source can also contribute to the plasma level. Prorenin should not be confused with large molecular weight forms of renal renin that have intrinsic enzymatic activity. These appear to be, at least in part, the result of binding of renin to a renal cortical protein. Plasma prorenin can be activated by the techniques of cryoactivation and acid activation. It can also be converted to active renin by neutral serine proteases such as trypsin, glandular kallikrein, plasma kallikrein, and plasmin, and by acid proteases such as pepsin and cathepsin D. Both cryoactivation and acid activation appear to be mediated, in part, by endogenous plasma kallikrein which converts prorenin to renin in plasma in vitro after either cold inactivation or acid destruction of plasma kallikrein inhibitors. ...

Prorenin and Other Large Molecular Weight Forms of Renin

Publisher Summary Plasma proteins form major transport systems as in the case of lipoproteins and iron-binding proteins or recognition systems as in the case of immunoglobulins; and they play important roles in the defense of the organism. In addition to the immunoglobulins, four major pathways of proteins in the plasma contribute to the host's capacity to defend against foreign substances, traumatic events, and internal disorders: they are the complement, contact (Hageman factor), extrinsic clotting, and fibrinolytic systems. These four systems have the capacity to act in concert and cross-activate one another. They may function as a direct or indirect consequence of immunologic activity. The investigations of the past 10 years have already shed considerable light on the interactions of proteins with surfaces and with other protein molecules and in the cascading conversion of proenzymes to their activated form. Inroads have also been made into the pathologic implications of the contact system when set into motion. In its most condensed form, the contact system consists of four proteins: Hageman factor (HF), prekallikrein, high-molecular-weight (MW) kininogen, and coagulation Factor XI. However, several other proteins may be involved.

The Biochemistry and Pathophysiology of the Contact System of Plasma

Increased activity is known to be present in the extrinsic, intrinsic, and final common pathways of the hemostatic system in men at high risk of coronary heart disease (CHD), but the status of the contact system of coagulation in this condition is uncertain. Plasma levels of activated factor XII (XIIa), the initial product of contact activation, have therefore been measured by ELISA in 2464 men aged 51 to 62 years, clinically free of CHD, who were taking part in a prospective cardiovascular survey based in general medical practices. Statistically significant, independent, and positive associations of XIIa were found with serum cholesterol and triglyceride concentrations, blood pressure, body mass index, factor VII activity, plasma fibrinogen concentration, and tobacco smoking, all associated with CHD. Plasma XIIa also increased with recent alcohol intake. Men in the highest quintile of risk according to their conventional risk factors had a mean XIIa of 2.07 ng/mL (95% confidence interval 1.99-2.16), 31% higher than that of men in the lowest quintile (1.58; 95% confidence interval 1.51-1.65). Thus, the contact system of coagulation appears to be activated when CHD risk is increased. Furthermore, the independent associations of XIIa with the major conventional CHD risk factors and its broad range of values in the general population (0.1 to 12.5 ng/mL), combined with a relatively low day-to-day variability in individuals (the within-person component of its total variation being 14.7%), suggest its potential usefulness as a marker of atherosclerotic vascular damage.

Risk of Coronary Heart Disease and Activation of Factor XII in Middle-Aged Men

Background—The relations of plasma activated factor XII (FXIIa) concentration and a common polymorphism (C46T) of the factor XII gene with hemostatic status and risk of coronary heart disease (CHD) were examined by prospective surveillance. Methods and Results—Genotyping for the C46T variant was performed in 2624 men 50 to 61 years of age who were free of CHD at baseline. The genotype distribution was as follows: CC, 56.7%; CT; 36.9%; and TT, 6.6%. Plasma FXIIa was measured by ELISA on 1745 samples collected 1 year after baseline; median levels were (ng/mL) CC, 2.0; CT, 1.4; and TT, 0.8 (P<0.0001). Respective values for plasma fibrinopeptide A (FPA, nmol/L) were 1.52, 1.35, and 1.15 (P<0.0001); for factor VII coagulant activity (FVIIc, % standard), 114.5, 116.2, and 109.3 (P=0.02). Group differences in FVIIc were unchanged by adjustment for body mass index and serum triglycerides. Whereas CHD incidence did not differ significantly by genotype, rates (per 1000 person-years) by thirds of FXIIa distribution ...

Epidemiological and genetic associations of activated factor XII concentration with factor VII activity, fibrinopeptide A concentration, and risk of coronary heart disease in men

EXPOSURE of normal human plasma to an activating (negatively charged) surface leads to the activation of the intrinsic coagulation system and the fibrinolytic system and the generation of vasoactive peptides (kinins)1,2. This contact activation mechanism is known to be initiated by factor XII (Hageman factor). Surface-activated factor XII converts prekallikrein (Fletcher factor) into kallikrein, which leads to further activation of factor XII. Prekallikrein circulates in plasma as a complex with the kallikrein substrate, high molecular weight kininogen, and the latter acts as a cofactor in the reciprocal activation of factor XII by kallikrein. The experiments described here demonstrate that the renin–angiotensin system is also activated by kallikrein through the factor XII-dependent pathway.

An intrinsic factor XII- prekallikrein-dependent pathway activates the human plasma renin-angiotensin system.

Kallikrein and plasmin as activators of inactive renin

New evidence for ancient Greek astronomer Hipparchus’ lost Star Catalogue has come to light thanks to multispectral imaging of a palimpsest manuscript and subsequent decipherment and interpretation. This new evidence is the most authoritative to date and allows major progress in the reconstruction of Hipparchus’ Star Catalogue. In particular, it confirms that the Star Catalogue was originally composed in equatorial coordinates. It also confirms that Ptolemy’s Star Catalogue was not based solely on data from Hipparchus’ Catalogue. Finally, the available numerical evidence is consistent with an accuracy within 1° of the real stellar coordinates, which would make Hipparchus’ Catalogue significantly more accurate than his successor Claudius Ptolemy’s.

https://doi.org/10.1177/00218286221128289

New evidence for Hipparchus’ Star Catalogue revealed by multispectral imaging

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E.A Zingg

Papers

Kallikrein and plasmin as activators of inactive renin

New evidence for Hipparchus’ Star Catalogue revealed by multispectral imaging

The Byzantine Platonists, 284-1453, edited by F. Lauritzen—S. Klitenic Wear